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1.  An Insight into Cervical Cancer Screening and Treatment Capacity in Sub-Saharan Africa 
OBJECTIVE
Approximately 85% of cervical cancer cases and deaths occur in resource-constrained countries where best practices for prevention, particularly for HIV-infected women, still need to be developed. The objective of this study was to assess cervical cancer prevention capacity in select HIV clinics located in resource-constrained countries.
METHODS
A cross-sectional survey of sub-Saharan African sites of four NIH-funded HIV/AIDS networks was conducted. Sites were surveyed on the availability of cervical cancer screening and treatment among HIV-infected and HIV-uninfected women. Descriptive statistics, and chi-square or Fisher’s exact test were used as appropriate.
RESULTS
Fifty-one out of 78 (65%) sites responded. Access to cervical cancer screening was reported by 49 (96%) sites. Of these sites, 39 (80%) performed screening on-site. Central African sites were less likely to have screening on-site (P= 0.02) versus other areas. Visual inspection with acetic acid (VIA) and Pap testing were the most commonly available on-site screening methods at 31 (79%) and 26 (67%) sites, respectively. High-risk HPV testing was available at 29% of sites with VIA and 50% of sites with Pap testing. Cryotherapy and radical hysterectomy were the most commonly available on-site treatment methods for premalignant and malignant lesions at 29 (74%) and 18 (46%) sites, respectively.
CONCLUSION
Despite limited resources, the majority of sites surveyed had the capacity to perform cervical cancer screening and treatment. The existing infrastructure of HIV clinical and research sites may provide the ideal framework for scale up of cervical cancer prevention in resource-constrained countries with a high burden of cervical dysplasia.
doi:10.1097/LGT.0000000000000165
PMCID: PMC4691409  PMID: 26579842
HIV; cervical cancer; Pap; HPV; VIA; resource-constrained country
2.  Evaluation of Performance Characteristics of the Aptima HIV-1 Quant Dx Assay for Detection and Quantitation of Human Immunodeficiency Virus Type 1 in Plasma and Cervicovaginal Lavage Samples 
Journal of Clinical Microbiology  2016;54(4):1036-1041.
Quantification of HIV-1 RNA has become the standard of care in the clinical management of HIV-1-infected individuals. The objective of this study was to evaluate performance characteristics and relative workflow of the Aptima HIV-1 Quant Dx assay in comparison with the Abbott RealTime HIV-1 assay using plasma and cervicovaginal lavage (CVL) specimens. Assay performance was evaluated by using an AcroMetrix HIV-1 panel, AcroMetrix positive controls, Qnostics and SeraCare HIV-1 evaluation panels, 208 clinical plasma samples, and 205 matched CVL specimens on the Panther and m2000 platforms. The Aptima assay demonstrated good linearity over the quantification range tested (2 to 5 log10 copies/ml), and there was strong linear correlation between the assays (R2 = 0.99), with a comparable coefficient of variance of <5.5%. For the plasma samples, Deming regression analyses and Bland-Altman plots showed excellent agreement between the assays, with an interassay concordance of 91.35% (kappa = 0.75; 95% confidence interval [CI], 0.65 to 0.85), and on average, the viral loads determined by the Aptima assay were 0.21 log10 copies/ml higher than those determined by the RealTime assay. The assays differed in their sensitivity for quantifying HIV-1 RNA loads in CVL samples, with the Aptima and RealTime assays detecting 30% and 20%, respectively. Aptima had fewer invalid results, and on average, the viral loads in CVL samples quantified by the Aptima assay were 0.072 log10 copies/ml higher than those of the RealTime assay. Our results demonstrate that the Aptima assay is sensitive and accurate in quantifying viral loads in both plasma and CVL specimens and that the fully automated Panther system has all the necessary features suitable for clinical laboratories demanding high-throughput sample processing.
doi:10.1128/JCM.03289-15
PMCID: PMC4809915  PMID: 26842702
3.  Assessment of Prevention of Mother-to-Child Transmission HIV Services in the Bantey Meanchey Province in Cambodia 
Background
Elimination of pediatric HIV requires a robust program for the prevention of mother-to-child transmission (PMTCT). The goal of this study was to assess the implementation of these services in Cambodia.
Methods
This prospective study was conducted in Bantey Meanchey at 2 sites. Staff reviewed daily clinic and laboratory registration logs to gather data on PMTCT service access among antenatal women.
Results
A total of 12 140 pregnant women received antenatal care. Only 4034 (33.2%) received pre-HIV test counseling. Of which 3407 (84.5%) received an HIV test. Eighteen (94.7%) of 19 women testing HIV-seropositive received triple-combination antiretroviral (ARV) medication. Fifteen HIV-exposed infants were delivered during the study. One infant tested HIV positive and is on ARV medication.
Conclusion
Acceptance for HIV testing was high among women who received pretest counseling. An increase in the number of counselors may improve the rates of HIV testing. Follow-up mechanisms targeting mother–baby pairs should focus on increasing timely service uptake in the public sector.
doi:10.1177/2325957415599208
PMCID: PMC4828308  PMID: 26337679
Cambodia; PMTCT; HIV
4.  Extragenital Infections Caused by Chlamydia trachomatis and Neisseria gonorrhoeae: A Review of the Literature 
In the United States, sexually transmitted diseases due to Chlamydia trachomatis and Neisseria gonorrhoeae continue to be a major public health burden. Screening of extragenital sites including the oropharynx and rectum is an emerging practice based on recent studies highlighting the prevalence of infection at these sites. We reviewed studies reporting the prevalence of extragenital infections in women, men who have sex with men (MSM), and men who have sex only with women (MSW), including distribution by anatomical site. Among women, prevalence was found to be 0.6–35.8% for rectal gonorrhea (median reported prevalence 1.9%), 0–29.6% for pharyngeal gonorrhea (median 2.1%), 2.0–77.3% for rectal chlamydia (median 8.7%), and 0.2–3.2% for pharyngeal chlamydia (median 1.7%). Among MSM, prevalence was found to be 0.2–24.0% for rectal gonorrhea (median 5.9%), 0.5–16.5% for pharyngeal gonorrhea (median 4.6%), 2.1–23.0% for rectal chlamydia (median 8.9%), and 0–3.6% for pharyngeal chlamydia (median 1.7%). Among MSW, the prevalence was found to be 0–5.7% for rectal gonorrhea (median 3.4%), 0.4–15.5% for pharyngeal gonorrhea (median 2.2%), 0–11.8% for rectal chlamydia (median 7.7%), and 0–22.0% for pharyngeal chlamydia (median 1.6%). Extragenital infections are often asymptomatic and found in the absence of reported risk behaviors, such as receptive anal and oral intercourse. We discuss current clinical recommendations and future directions for research.
doi:10.1155/2016/5758387
PMCID: PMC4913006  PMID: 27366021
5.  Pregnancy Desire, Partner Serodiscordance, and Partner HIV Disclosure among Reproductive Age HIV-Infected Women in an Urban Clinic 
Women comprise 25% of the US HIV epidemic, with many women of reproductive age. There is a need for providers to address the reproductive needs and desires of women with HIV given that effective antiretroviral therapy has transformed HIV into a chronic disease. This cross-sectional study shows high rates of partner serodiscordance (61%) and moderate HIV disclosure to partners (61%). Patients surveyed reported practitioners discuss condoms (94%) and contraception (71%) more often than pregnancy desire (38%). In our sample, 44% of the surveyed women intended future pregnancy, whereas women who did not intend future pregnancy cited HIV/health and serodiscordance as the most common reasons (56% and 35%, resp.). There was no difference in the knowledge of mother-to-child transmission risk between women who intended or did not intend future pregnancy (p = 0.71). These results underline the need for provider training in reproductive counseling to promote risk reduction and education.
doi:10.1155/2016/8048457
PMCID: PMC4899585  PMID: 27313441
6.  Human Papillomavirus Vaccination in HIV-infected Women: Need for Increased Coverage 
Expert review of vaccines  2015;15(1):105-117.
HIV-infected women carry a significant burden on HPV infection and associated diseases. As HIV-infected individuals are living longer, the prevalence of HPV infection is rising and HPV-associated cytologic abnormalities remain high despite successful treatments of HIV infection. Several HPV vaccines are currently available and recommended for adolescents and adults up to age 26. The vaccine is safe, immunogenic and effective in preventing diseases due to HPV types included in the vaccines, particularly among persons without prior HPV exposure. This review summarizes available data on the use of the HPV vaccines among HIV infected women. The immunogenicity and safety of the vaccine is highlighted and in particular, barriers to vaccination among HIV infected women are discussed.
doi:10.1586/14760584.2016.1110025
PMCID: PMC4825670  PMID: 26599305
7.  Immunogenicity and Safety of the Quadrivalent Human Papillomavirus Vaccine in HIV-1–Infected Women 
This multicenter prospective trial among HIV-1–infected women aged 13–45 years found that the quadrivalent human papillomavirus vaccine was highly immunogenic, but women with CD4 counts <200 cells/µL had lower seroconversion rates compared with women with higher CD4 cell counts.
Background. Women infected with human immunodeficiency virus (HIV) are disproportionately affected by human papillomavirus (HPV)–related anogenital disease, particularly with increased immunosuppression. AIDS Clinical Trials Group protocol A5240 was a trial of 319 HIV-infected women in the United States, Brazil, and South Africa to determine immunogenicity and safety of the quadrivalent HPV vaccine in 3 strata based on screening CD4 count: >350 (stratum A), 201–350 (stratum B), and ≤200 cells/µL (stratum C).
Methods. Safety and serostatus of HPV types 6, 11, 16, and 18 were examined. HPV serological testing was performed using competitive Luminex immunoassay (HPV-4 cLIA). HPV type-specific seroconversion analysis was done for participants who were seronegative for the given type at baseline.
Results. Median age of patients was 36 years; 11% were white, 56% black, and 31% Hispanic. Median CD4 count was 310 cells/µL, and 40% had undetectable HIV-1 load. No safety issues were identified. Seroconversion proportions among women at week 28 for HPV types 6, 11,16, and 18 were 96%, 98%, 99%, and 91%, respectively, for stratum A; 100%, 98%, 98%, and 85%, respectively, for stratum B, and 84%, 92%, 93%, and 75%, respectively, for stratum C.
Conclusions. The quadrivalent HPV vaccine targeted at types 6, 11, 16, and 18 was safe and immunogenic in HIV-infected women aged 13–45 years. Women with HIV RNA load >10 000 copies/mL and/or CD4 count <200 cells/µL had lower rates of seroconversion rates.
Clinical Trials Registration. NCT00604175.
doi:10.1093/cid/ciu238
PMCID: PMC4305143  PMID: 24723284
HPV vaccine; HIV-infected women; immunogenicity; vaccine safety; anogenital disease
8.  Acceptance of HIV Antibody Testing Among Women in Domestic Violence Shelters 
The purpose of this study was to examine which factors derived from an adapted version of the Health Belief Model are associated with HIV testing among women at domestic violence shelters in the rural south (N = 112). Participants were administered self-report questionnaires to assess for test acceptance and were offered private and free HIV rapid testing. A logistic regression analysis was performed. Results indicated that higher perceived susceptibility and higher PTSD symptoms predicted a greater likelihood of HIV test acceptance. The most common reason given for not testing was a lack of time. Implications are discussed.
doi:10.1080/15381501.2012.703555
PMCID: PMC4467823  PMID: 26085820
Rapid HIV testing; domestic violence; intimate partner violence; HIV and IPV
9.  Care of the HIV-infected pregnant woman in the developed world 
Obstetric Medicine  2015;8(1):13-17.
The reduction of human immunodeficiency virus (HIV) transmission from mother to child is one of the success stories of modern medicine and public health. In the developed world, with universal HIV counseling and testing, antiretroviral prophylaxis, scheduled Caesarean delivery if indicated, and avoidance of breastfeeding, HIV transmission from mother to infant can be <2%. Despite this, transmissions continue to occur, often due to lack of knowledge of HIV status. Missed opportunities for prevention and prevention challenges include late prenatal care, lack of HIV testing in pregnancy, lack of preconception counseling, unintended pregnancy, and substance abuse. We review preconception counseling including options for serodiscordant couples, and antepartum, peripartum and postpartum care of the HIV-infected woman in the developed world, and advocate for a comprehensive, collaborative, multidisciplinary approach.
doi:10.1177/1753495X14531753
PMCID: PMC4934996  PMID: 27512453
Infectious diseases; immunology; high-risk pregnancy; maternal fetal medicine
10.  The Spectrum of Undiagnosed Hepatitis C Virus Infection in a US HIV Clinic 
AIDS Patient Care and STDs  2014;28(1):4-9.
Abstract
United States guidelines endorse one-time HCV antibody screening at HIV diagnosis. Rescreening HCV-seronegative patients on a regular basis is still not policy, although HIV-infected persons have reasonably substantial HCV incidence. We evaluated routine risk factor-independent HCV antibody re-testing in a Rhode Island HIV clinic. We instituted annual HCV antibody testing for HCV-seronegative patients who had not been rescreened in a year or more. Testing based on clinical suspicion continued. We conducted a chart review of new antibody-positive cases in the first year of rescreening, July 2006 to June 2007. Of 245 rescreened patients, 11 (4.5%) seroconverted. Five (45%) were female. Median time between last negative and first positive result was 32 months (range 8–98 months). Six (55%) had documented risk factors and 6 (55%) elevated ALT (>45 IU/L) between antibody tests; none prompted re-testing. One seroconverter died of hepatocellular carcinoma 3.7 years after HCV diagnosis. A twelfth was rescreened for suspected acute HCV based on ALT of 515 IU/L. He had newly detectable HCV RNA then seroconversion, and achieved SVR following 6 months of treatment in the acute phase for genotype 1 infection. Incident HCV is not uncommon among HIV-infected patients in care. Rescreening identified undiagnosed HCV in this population. HCV RNA should be checked promptly in HCV-seronegative persons with ALT elevation. We observed consequences of late diagnosis (hepatocellular carcinoma) and benefits of early diagnosis (cure with treatment of acute HCV). Adding annual rescreening to the Ryan White Program would facilitate earlier identification of undiagnosed HCV and create an instant widespread surveillance system, providing HCV incidence data.
doi:10.1089/apc.2013.0130
PMCID: PMC3894677  PMID: 24428794
11.  Changes in HIV-1 Subtypes B and C Genital Tract RNA in Women and Men After Initiation of Antiretroviral Therapy 
Fiscus, Susan A. | Cu-Uvin, Susan | Eshete, Abel Tilahun | Hughes, Michael D. | Bao, Yajing | Hosseinipour, Mina | Grinsztejn, Beatriz | Badal-Faesen, Sharlaa | Dragavon, Joan | Coombs, Robert W. | Braun, Ken | Moran, Laura | Hakim, James | Flanigan, Timothy | Kumarasamy, N. | Campbell, Thomas B. | Klingman, Karin L. | Nair, Apsara | Walawander, Ann | Smeaton, Laura M. | De Gruttola, Victor | Martinez, Ana I. | Swann, Edith | Barnett, Ronald L. | Brizz, Barbara | Delph, Yvette | Gettinger, Nikki | Mitsuyasu, Ronald T. | Eshleman, Susan | Safren, Steven | Andrade, Adriana | Haas, David W. | Amod, Farida | Berthaud, Vladimir | Bollinger, Robert C. | Bryson, Yvonne | Celentano, David | Chilongozi, David | Cohen, Myron | Collier, Ann C. | Currier, Judith Silverstein | Eron, Joseph | Firnhaber, Cynthia | Flexner, Charles | Gallant, Joel E. | Gulick, Roy M. | Hammer, Scott M. | Hoffman, Irving | Kazembe, Peter | Kumwenda, Johnstone | Kumwenda, Newton | Lama, Javier R. | Lawrence, Jody | Maponga, Chiedza | Martinson, Francis | Mayer, Kenneth | Nielsen, Karin | Pendame, Richard B. | Ramratnam, Bharat | Rooney, James F. | Sanchez, Jorge | Sanne, Ian | Schooley, Robert T. | Snowden, Wendy | Solomon, Suniti | Tabet, Steve | Taha, Taha | Uy, Jonathan | van der Horst, Charles | Wanke, Christine | Gormley, Joan | Marcus, Cheryl J. | Putnam, Beverly | Ntshele, Smanga | Loeliger, Edde | Pappa, Keith A. | Webb, Nancy | Shugarts, David L. | Winters, Mark A. | Descallar, Renard S. | Sharma, Jabin | Poongulali, S. | Cardoso, Sandra Wagner | Faria, Deise Lucia | Berendes, Sima | Burke, Kelly | Kanyama, Cecelia | Kayoyo, Virginia | Samaneka, Wadzanai P. | Chisada, Anthony | Santos, Breno | La Rosa, Alberto | Infante, Rosa | Balfour, Henry H. | Mullan, Beth | Kim, Ge-Youl | Klebert, Michael K. | Mildvan, Donna | Revuelta, Manuel | Jan Geiseler, P. | Santos, Bartolo | Daar, Eric S. | Lopez, Ruben | Frarey, Laurie | Currin, David | Haas, David H. | Bailey, Vicki L. | Tebas, Pablo | Zifchak, Larisa | Sha, Beverly E. | Fritsche, Janice M.
Women with human immunodeficiency virus (HIV)–1 subtype C had significantly higher genital tract viral loads compared to women with HIV-1 subtype B and men with HIV-1 subtype C or B. Women in general were significantly less likely to have genital tract viral load below the lower limit of quantification compared to men.
Background. Combination antiretroviral therapy (cART) reduces genital tract human immunodeficiency virus type 1 (HIV-1) load and reduces the risk of sexual transmission, but little is known about the efficacy of cART for decreasing genital tract viral load (GTVL) and differences in sex or HIV-1 subtype.
Methods. HIV-1 RNA from blood plasma, seminal plasma, or cervical wicks was quantified at baseline and at weeks 48 and 96 after entry in a randomized clinical trial of 3 cART regimens.
Results. One hundred fifty-eight men and 170 women from 7 countries were studied (men: 55% subtype B and 45% subtype C; women: 24% subtype B and 76% subtype C). Despite similar baseline CD4+ cell counts and blood plasma viral loads, women with subtype C had the highest GTVL (median, 5.1 log10 copies/mL) compared to women with subtype B and men with subtype C or B (4.0, 4.0, and 3.8 log10 copies/mL, respectively; P < .001). The proportion of participants with a GTVL below the lower limit of quantification (LLQ) at week 48 (90%) and week 96 (90%) was increased compared to baseline (16%; P < .001 at both times). Women were significantly less likely to have GTVL below the LLQ compared to men (84% vs 94% at week 48, P = .006; 84% vs 97% at week 96, P = .002), despite a more sensitive assay for seminal plasma than for cervical wicks. No difference in GTVL response across the 3 cART regimens was detected.
Conclusions. The female genital tract may serve as a reservoir of persistent HIV-1 replication during cART and affect the use of cART to prevent sexual and perinatal transmission of HIV-1.
doi:10.1093/cid/cit195
PMCID: PMC3689341  PMID: 23532477
HIV-1 genital tract RNA; HIV-1 subtypes B and C; antiretroviral drugs
12.  Dense Genotyping of Immune-Related Loci Identifies Variants Associated with Clearance of HPV among HIV-Positive Women in the HIV Epidemiology Research Study (HERS) 
PLoS ONE  2014;9(6):e99109.
Persistent high-risk human papillomavirus (HR-HPV) is a necessary and causal factor of cervical cancer. Most women naturally clear HPV infections; however, the biological mechanisms related to HPV pathogenesis have not been clearly elucidated. Host genetic factors that specifically regulate immune response could play an important role. All HIV-positive women in the HIV Epidemiology Research Study (HERS) with a HR-HPV infection and at least one follow-up biannual visit were included in the study. Cervicovaginal lavage samples were tested for HPV using type-specific HPV hybridization assays. Type-specific HPV clearance was defined as two consecutive HPV-negative tests after a positive test. DNA from participants was genotyped for 196,524 variants within 186 known immune related loci using the custom ImmunoChip microarray. To assess the influence of each single-nucleotide polymorphism (SNP) with HR-HPV clearance, the Cox proportional hazards model with the Wei-Lin-Weissfeld approach was used, adjusting for CD4+ count, low risk HPV (LR-HPV) co-infection, and relevant confounders. Three analytical models were performed: race-specific (African Americans (n = 258), European Americans (n = 87), Hispanics (n = 55), race-adjusted combined analysis, and meta-analysis of pooled independent race-specific analyses. Women were followed for a median time of 1,617 days. Overall, three SNPs (rs1112085, rs11102637, and rs12030900) in the MAGI-3 gene and one SNP (rs8031627) in the SMAD3 gene were associated with HR-HPV clearance (p<10−6). A variant (rs1633038) in HLA-G were also significantly associated in African American. Results from this study support associations of immune-related genes, having potential biological mechanism, with differential cervical HR-HPV infection outcomes.
doi:10.1371/journal.pone.0099109
PMCID: PMC4053382  PMID: 24918582
13.  HIV-1 RNA Levels and Antiretroviral Drug Resistance in Blood and Non-Blood Compartments from HIV-1–Infected Men and Women enrolled in AIDS Clinical Trials Group Study A5077 
PLoS ONE  2014;9(4):e93537.
Background
Detectable HIV-1 in body compartments can lead to transmission and antiretroviral resistance. Although sex differences in viral shedding have been demonstrated, mechanisms and magnitude are unclear. We compared RNA levels in blood, genital-secretions and saliva; and drug resistance in plasma and genital-secretions of men and women starting/changing antiretroviral therapy (ART) in the AIDS Clinical Trials Group (ACTG) 5077 study.
Methods
Blood, saliva and genital-secretions (compartment fluids) were collected from HIV-infected adults (≥13 years) at 14 United-States sites, who were initiating or changing ART with plasma viral load (VL) ≥2,000 copies/mL. VL testing was performed on all compartment fluids and HIV resistance genotyping on plasma and genital-secretions. Spearman rank correlations were used to evaluate concordance and Fisher’s and McNemar’s exact tests to compare VL between sexes and among compartments.
Results
Samples were available for 143 subjects; 36% treated (23 men, 29 women) and 64% ‘untreated’ (40 men, 51 women). RNA detection was significantly more frequent in plasma (100%) than genital-secretions (57%) and saliva (64%) (P<0.001). A higher proportion of men had genital shedding versus women (78% versus 41%), and RNA detection was more frequent in saliva versus genital-secretions in women when adjusted for censoring at the limit of assay detection. Inter-compartment fluid VL concordance was low in both sexes. In 22 (13 men, 9 women) paired plasma-genital-secretion genotypes from treated subjects, most had detectable resistance in both plasma (77%) and genital-secretions (68%). Resistance discordance was observed between compartments in 14% of subjects.
Conclusions
HIV shedding and drug resistance detection prior to initiation/change of ART in ACTG 5077 subjects differed among tissues and between sexes, making the gold standard blood-plasma compartment assessment not fully representative of HIV at other tissue sites. Mechanisms of potential sex-dependent tissue compartmentalization should be further characterized to aid in optimizing treatment and prevention of HIV transmission.
Trial Registration
ClinicalTrials.gov NCT00007488
doi:10.1371/journal.pone.0093537
PMCID: PMC3974754  PMID: 24699474
14.  Pregnancy-induced changes in immune protection of the genital tract: defining normal 
Introduction
Both the state of pregnancy as well as disruption of vaginal flora and immune mediators may increase the risk of human immunodeficiency virus (HIV)-1 acquisition.. The objective of this study was to define immune changes in lower genital and systemic immunity associated with normal pregnancy.
Methods
Prospective cohort enrolled low risk pregnant and non-pregnant women ages 18 to 35. Pregnant women at < 14 weeks and non-pregnant women in follicular phase of the menstrual cycle were included. Cervical and vaginal fluid was collected. Concentrations of immune mediators were measured using ELISA-based methods or multiplex immunoassay. Samples were inoculated onto various culture media allowing for growth of Lactobacillus spp, G. vaginalis, E.coli, Enterococcus spp, anaerobic gramnegative rods, Candida, S. aureus, Ureaplasma spp, and Mycoplasma hominis. Concentrations of immune mediators and vaginal colonization frequencies were compared between the pregnant and non-pregnant groups.
Results
Genital tract concentration of IL-1β was higher during pregnancy compared to non-pregnant participants. Serum CRP concentrations were higher in all trimesters of pregnancy. Concentrations of secretory leukocyte protease inhibitor didn’t differ between groups. Lactobacillus was more commonly isolated from vaginal cultures of non-pregnant participants (100% vs. 70.2%, p=0.02). Identification of Candida, G. vaginalis, M. hominis and S. aureus was common and not different between groups. Ureaplasma spp was isolated from over 60% pregnant participants.
Conclusions
The pro-inflammatory cytokine, IL-1β, as well as the systemic marker of inflammation, CRP, are increased during pregnancy. The impact of these pro-inflammatory changes during pregnancy deserves further study.
doi:10.1016/j.ajog.2013.01.014
PMCID: PMC3610848  PMID: 23313311
Pregnancy; genital flora; vaginal immunity; inflammation; cytokines
15.  Persistent Genital Tract HIV-1 RNA Shedding After Change in Treatment Regimens in Antiretroviral-Experienced Women with Detectable Plasma Viral Load 
Journal of Women's Health  2013;22(4):330-338.
Abstract
Objective
To longitudinally assess the association between plasma viral load (PVL) and genital tract human immunodeficiency virus (GT HIV) RNA among HIV-1 infected women changing highly active antiretroviral therapy (HAART) because of detectable PVL on current treatment.
Methods
Women were eligible for the study if they had detectable PVL (defined as two consecutive samples with PVL>1000 copies/mL) and intended to change their current HAART regimen at the time of enrollment. Paired plasma and GT HIV-1 RNA were measured prospectively over 3 years. Longitudinal analyses examined rates of GT HIV-1 RNA shedding and the association with PVL.
Results
Sixteen women were followed for a median of 11 visits contributing a total of 205 study visits. At study enrollment, all had detectable PVL and 69% had detectable GT HIV-1 RNA. Half of the women changed to a new HAART regimen with ≥3 active antiretroviral drugs. The probability of having detectable PVL ≥30 days after changing HAART was 0.56 (95% CI: 0.37 to 0.74). Fourteen women (88%) had detectable PVL on a follow-up visit ≥30 or 60 days after changing HAART; and 12 women (75%) had detectable GT HIV-1 RNA on a follow-up visit ≥30 or 60 days after changing HAART. When PVL was undetectable, GT shedding occurred at 11% of visits, and when PVL was detectable, GT shedding occurred at 47% of visits.
Conclusions
Some treatment-experienced HIV-infected women continue to have detectable virus in both the plasma and GT following a change in HAART, highlighting the difficulty of viral suppression in this patient population.
doi:10.1089/jwh.2012.3849
PMCID: PMC3627435  PMID: 23531097
16.  Genital Tract Viral Load in HIV Type 1-Positive Women Correlates with Specific Cytokine Levels in Cervical-Vaginal Secretions But Is Not a Determinant of Infectious Virus or Anti-HIV Activity 
AIDS Research and Human Retroviruses  2012;28(11):1533-1539.
Abstract
As the AIDS epidemic continues with women being disproportionately affected, it is crucial to understand factors that predict the risk of heterosexual HIV-1 transmission. We investigated whether genital tract viral load (GTVL) in cervical-vaginal lavages (CVL) from HIV-1-positive women with moderately low CD4 T cell counts correlates with cytokine levels, antimicrobial concentrations, and intrinsic anti-HIV activity. CVL were collected from 19 HIV-1-positive women with moderately low CD4 T cell counts [mean 381 cells/mm3 (227–536 cells/mm3)]. None of the women was on antiretroviral therapy. The women were categorized into those with detectable GTVL or those with undetectable GTVL (detectable GTVL RNA levels > 400 copies/ml). Women were also categorized according to bacterial vaginosis (BV) status irrespective of GTVL. The TZM-bl assay was used to determine the presence of infectious virus and anti-HIV activity. Significantly higher levels of RANTES, Eotaxin, Fractalkine, IL-1α, IL-6, MCP-1, MIP1β, MIP1α, TNF-α, and GM-CSF were observed in women with detectable GTVL compared to women with undetectable GTVL. No significant differences were observed in the following cytokines and chemokines: G-CSF, IL-1RA, IL-8, and IP-10. GTVL did not correlate either with antimicrobials known to have anti-HIV activity or with the presence of infectious virus. BV status did not have a significant effect on anti-HIV activity. These findings further our understanding of the role of GTVL in determining the cytokine and chemokine milieu in the female reproductive tract.
doi:10.1089/aid.2011.0394
PMCID: PMC3484767  PMID: 22356616
17.  Effect of trichomoniasis therapy on genital HIV viral burden among African women 
Sexually Transmitted Diseases  2012;39(8):638-642.
Background
Our objective was to test the hypothesis that treatment for trichomoniasis among HIV-infected women not taking antiretrovirals in South Africa would be associated with decreased HIV genital shedding.
Methods
HIV-infected women presenting for routine HIV care were screened for trichomoniasis using self-collected vaginal swabs with a rapid point-of-care immunochromatographic antigen test. Women testing positive were offered enrollment into a prospective cohort study if they had documented HIV infection, were ages 18–50, and not receiving antiretroviral therapy. Recent use of post-exposure prophylaxis or antibiotic therapy, active genital ulcers, or systemic illness were exclusion criteria. Cervical swabs were collected for gonococcal and chlamydial testing and those testing positive were excluded. Women were treated with directly-observed oral therapy with 2 grams of oral metronidazole. A follow-up visit was scheduled one month after therapy and partner letters were provided. Paired cervical wicks and plasma were collected for viral load measurement.
Results
557 women were screened. 60 tested positive for trichomoniasis, 10 subsequently met exclusion criteria, 4 were lost to follow-up. Of 46 women evaluated at follow-up, 37 were cured, 80.4%. Plasma viral load was not significantly different after therapy, p=0.93. Genital tract viral load decreased by 0.5 log10, p<0.01. The mean genital tract viral load (log10) decreased from 4.66 (<3.52 – 6.46) to 4.18 (<3.52 – 6.48), p<0.01 following therapy.
Conclusions
Screening and treatment of vaginal trichomoniasis decreases genital shedding of HIV among South African women not receiving antiretrovirals at one month following therapy.
doi:10.1097/OLQ.0b013e31825725ad
PMCID: PMC3398383  PMID: 22797689
HIV; trichomoniasis; women; genital shedding; metronidazole
18.  Clinical Parameters Essential to Methodology and Interpretation of Mucosal Responses 
Research aimed at putting an end to the HIV pandemic is dynamic given the marked advances in understanding of pathogenesis since its origin. Attention has shifted from systemic management of disease to a focus on the most common site of acquisition, the female genital tract. Research on the female genital tract of humans requires consideration of a number of specific clinical parameters. If such parameters are not considered when enrolling subjects into studies, it could lead to faulty data ascertainment. This article reviews important clinical characteristics to consider when conducting studies of the human female genital tract in regard to mucosal immunity and HIV disease. Important topics to consider include the method and source of sample collection, the individual patient characteristics, and in the case of recruitment of HIV-infected women, HIV disease characteristics.
doi:10.1111/j.1600-0897.2010.00947.x
PMCID: PMC3716291  PMID: 21223419
Clinical parameters; female genital tract; HIV; mucosal immunity
19.  In vitro anti-HIV-1 activity in cervicovaginal secretions from pregnant and non-pregnant women 
Objective
To evaluate whether cervicovaginal secretions inhibit HIV-1 infectivity in an in vitro model, and estimate concentration of immune mediators.
Study design
We enrolled mid-trimester pregnant and regularly menstruating (non-pregnant) women. Cervicovaginal lavage (CVL) was collected at 2 visits and incubated with HIV-1 and TZM-bl cells. Infectivity was compared to positive controls. Concentrations of immune mediators were compared between groups.
Results
At enrollment, CVL inhibited IIIB virus 88.2% and 82.4%, and BaL virus 72.8% and 77.9%, among pregnant (n=13) and non-pregnant women (n=9), respectively. At second visit, CVL inhibited IIIB 89.7% and 82.5%, and BaL 77.4% and 69.9% among pregnant (n=15) and non-pregnant women (n=8), respectively (all P ≤ 0.04). Adjusting for body mass index, race, and protein content of CVL, antimicrobials were suppressed but cytokines and chemokines were not markedly different in pregnancy.
Conclusion
Cervicovaginal secretions significantly suppress HIV-1 infectivity in this model. Concentrations of certain immune mediators are altered in pregnancy.
doi:10.1016/j.ajog.2012.04.029
PMCID: PMC3383647  PMID: 22727351
cervicovaginal lavage; cervicovaginal secretions; HIV; pregnancy
20.  Association of HIV Viral Load and CD4 with HPV Detection and Clearance in HIV Infected Women Initiating HAART 
HIV medicine  2012;13(6):372-378.
Objectives
The extent to which highly active antiretroviral therapy (HAART) affects HPV acquisition and clearance in HIV-infected women is not well-understood. We sought to describe high risk HPV detection and clearance rates over time since HAART initiation, based on time-varying HIV viral load (VL) and CD4+ T-cell count (CD4) using novel statistical methods.
Methods
We conducted retrospective analysis of data from completed AIDS Clinical Trials Group (ACTG) A5029 study using multi-state Markov models. Two sets of high risk HPV types from 2003 and 2009 publications were considered.
Results
There was some evidence that VL>400 copies/mL was marginally associated with higher rate of HPV detection (p=0.068, hazard ratio [HR]=4.67), using the older set of high risk HPV types. Such association was not identified using the latest set of HPV types (p=0.343, HR=2.64). CD4>350 cells/mm3 was significantly associated with more rapid HPV clearance with both sets of HPV types (p=0.001, HR=3.93; p=0.018, HR=2.65). There was no evidence that HPV affects VL or CD4 in all analyses.
Conclusions
High risk HPV types vary in studies, and they can affect analysis results. Use of HAART to improve CD4 may have an impact in the control of HPV infection, and the decrease in VL to a lesser degree.
doi:10.1111/j.1468-1293.2011.00979.x
PMCID: PMC3500098  PMID: 22257000
HIV; human papillomavirus; HAART; cervical cancer; Markov models
21.  Antiretrovirals and safer conception for HIV-serodiscordant couples 
Current opinion in HIV and AIDS  2012;7(6):569-578.
Purpose of review
Many men and women living with HIV and their uninfected partners attempt to conceive children. HIV-prevention science can be applied to reduce sexual transmission risk while respecting couples’ reproductive goals. Here we discuss antiretrovirals as prevention in the context of safer conception for HIV-serodiscordant couples.
Recent findings
Antiretroviral therapy (ART) for the infected partner and pre-exposure prophylaxis (PrEP) for the uninfected partner reduce the risk of heterosexual HIV transmission. Several demonstration projects suggest the feasibility and acceptability of antiretroviral (ARV)s as periconception HIV-prevention for HIV-serodiscordant couples. The application of ARVs to periconception risk reduction may be limited by adherence.
Summary
For male-infected (M+F−) couples who cannot access sperm processing and female-infected (F+M−) couples unwilling to carry out insemination without intercourse, ART for the infected partner, PrEP for the uninfected partner, combined with treatment for sexually transmitted infections, sex limited to peak fertility, and medical male circumcision (for F+M couples) provide excellent, well tolerated options for reducing the risk of periconception HIV sexual transmission.
doi:10.1097/COH.0b013e328358bac9
PMCID: PMC3695736  PMID: 23032734
antiretrovirals as prevention; conception; fertility; HIV prevention; HIV-serodiscordance; perinatal HIV transmission; sexual HIV transmission
22.  Infant Outcomes After Maternal Antiretroviral Exposure in Resource-Limited Settings 
Pediatrics  2012;129(6):e1525-e1532.
BACKGROUND AND OBJECTIVE:
The impact of maternal antiretrovirals (ARVs) during pregnancy, labor, and postpartum on infant outcomes is unclear.
METHODS:
Infants born to HIV-infected mothers in ARV studies were followed for 18 months.
RESULTS:
Between June 2006 and December 2008, 236 infants enrolled from Africa (n = 36), India (n = 47), Thailand (n = 152), and Brazil (n = 1). Exposure to ARVs in pregnancy included ≥3 ARVs (10%), zidovudine/intrapartum ARV (81%), and intrapartum ARV (9%). There were 4 infant infections (1 in utero, 3 late postpartum) and 4 deaths with 1.8% mortality (95% confidence interval [CI], 0.1%–3.5%) and 96.4% HIV-1–free survival (95% CI, 94.0%–98.9%). Birth weight was ≥2.5 kg in 86%. In the first 6 months, Indian infants (nonbreastfed) had lowest median weights and lengths and smallest increases in growth. After 6 months, African infants had the lowest median weight and weight-for-age z scores. Infants exposed to highest maternal viral load had the lowest height and height-for-age z scores. Serious adverse events occurred in 38% of infants, did not differ by country, and correlated with less maternal ARV exposure. Clinical diagnoses were seen in 84% of Thai, 31% of African, and 9% of Indian infants. Congenital defects/inborn errors of metabolism were seen in 18 (7.6%) infants, of which 17 were Thai (11%: 95% CI, 6.7%–17.0%); none had first trimester ARV exposure.
CONCLUSIONS:
Infant follow-up in large international cohorts is feasible and provides important safety and HIV transmission data following maternal ARV exposure. Increased surveillance increases identification of congenital/inborn errors.
doi:10.1542/peds.2011-2340
PMCID: PMC3362906  PMID: 22585772
maternal ARV exposure; infant safety; ARV toxicities; A5190; P1054; MTCT; HIV
23.  HIV-1 Sero-Prevalence and Awareness of Mother-to-Child Transmission Issues Among Women Seeking Antenatal Care in Tamil Nadu, India 
Background
Despite increasing availability of HIV-1 testing, education, and methods to prevent transmission, Indian women and their children remain at risk of acquiring HIV. We assessed the sero-prevalence and awareness about HIV among pregnant women presenting to a private tertiary care hospital in South India.
Methods
Sero-prevalence was determined via enzyme-linked immunosorbent assay (ELISA) testing, and questionnaires were analyzed using chi-square statistics and odds ratios to look for factors associated with HIV positivity.
Results
A total of 7956 women who presented for antenatal care were interviewed. Fifty-one women of the 7235 women who underwent HIV testing (0.7%) were found to be HIV positive. Awareness of mother-to-child transmission (MTCT) of HIV (64%), HIV transmission through breast milk (42%), and prevention of MTCT (13%) was low.
Conclusions
There is a need to educate South Indian women about HIV to give them information and the means to protect themselves and their unborn children from acquiring HIV.
doi:10.1177/1545109710371132
PMCID: PMC3652013  PMID: 20530464
HIV; sero-prevalence; awareness; pregnancy; antenatal; India
24.  Comparison of Conventional Cervical Cytology versus Visual Inspection with Acetic Acid (VIA) among HIV-Infected Women in Western Kenya 
Objective
To determine the accuracy of visual inspection with Acetic Acid (VIA) versus conventional Pap smear as a screening tool for cervical intraepithelial neoplasia (CIN)/cancer among HIV-infected women.
Materials and Methods
150 HIV-infected women attending the Moi Teaching and Referral Hospital HIV clinic in Eldoret underwent conventional Pap smear, VIA, colposcopy and biopsy. VIA and Pap smears were done by nurses while colposcopy and biopsy were done by a physician. Receiver Operating Characteristic (ROC) analysis was conducted to compare the accuracies between VIA and Pap smear in sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).
Results
Among the study participants: VIA was abnormal in 55.3% (83/150, CI=47.0–63.5%); Pap smear showed atypical squamous cells of undetermined significance (ASCUS) or worse in 43.7% (59/135, CI=35.2–52.5%) and 10% (15/150) of the Pap smears were unsatisfactory. Of the abnormal Pap smears, 3% (2/59) had ASCUS, 7% (4/59) had ASC-high grade, 60% (35/59) had low-grade squamous intraepithelial lesions (SIL), 29% (17/59) had high grade SIL, and 2% (1/59) was suspicious for cervical cancer. Using cervical intraepithelial neoplasia (CIN) 2 or higher disease on biopsy as an end point, VIA has a sensitivity of 69.6% (CI=55.1–81.0%), specificity of 51.0% (CI=41.5–60.4%), PPV of 38.6% (CI=28.8–49.3%) and NPV of 79.1% (CI=67.8–87.2%). For conventional Pap smear, sensitivity was 52.5% (CI=42.1–71.5%), specificity 66.3% (CI=52.0–71.2%), PPV 39.7% (CI=27.6–51.8%), and NPV 76.8% (CI=67.0–85.6%).
Conclusion
VIA is comparable to Pap smear and acceptable for screening HIV-infected women in resource limited settings such as Western Kenya.
doi:10.1097/LGT.0b013e3182320f0c
PMCID: PMC3289722  PMID: 22126834
Visual Inspection with Acetic Acid (VIA); Pap smear; Kenya; HIV

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