Warren Phipps

Pregnancy Complications Associated with Hepatitis C: Data from a 2003–2005 Washington State Birth Cohort

OBJECTIVE The objective of the study was to determine the effect of hepatitis C virus (HCV) on selected maternal and infant birth outcomes. STUDY DESIGN This population-based cohort study using Washington state birth records from 2003 to 2005 compared a cohort of pregnant women identified as HCV positive from birth certificate data (n = 506) to randomly selected HCV-negative mothers (n = 2022) and drug-using HCV-negative mothers (n = 1439). RESULTS Infants of HCV-positive mothers were more likely to be low birthweight (odds ratio [OR], 2.17; 95% confidence interval [CI] 1.24, 3.80), to be small for gestational age (OR, 1.46; 95% CI, 1.00, 2.13), to need assisted ventilation (OR, 2.37; 95% CI, 1.46, 3.85), and to require neonatal intensive car unit (NICU) admission (OR, 2.91; 95% CI, 1.86, 4.55). HCV-positive mothers with excess weight gain also had a greater risk of gestational diabetes (OR, 2.51; 95% CI, 1.04, 6.03). Compared with the drug-using cohort, NICU admission and the need for assisted ventilation remained associated with HCV. CONCLUSION HCV-positive pregnant women appear to be at risk for adverse neonatal and maternal outcomes.

Persistent Genital Herpes Simplex Virus-2 Shedding Years Following the First Clinical Episode

BACKGROUND Patients with newly acquired genital herpes simplex virus 2 (HSV-2) infection have virus frequently detected at the genital mucosa. Rates of genital shedding initially decrease over time after infection, but data on long-term viral shedding are lacking. METHODS For this study, 377 healthy adults with history of symptomatic genital HSV-2 infection collected anogenital swabs for HSV-2 DNA polymerase chain reaction for at least 30 consecutive days. RESULTS Time since first genital herpes episode was significantly associated with reduced genital shedding. Total HSV shedding occurred on 33.6% of days in participants <1 year, 20.6% in those 1-9 years, and 16.7% in those ≥10 years from first episode. Subclinical HSV shedding occurred on 26.2% of days among participants <1 year, 13.1% in those 1-9 years, and 9.3% in those ≥10 years from first episode. On days with HSV detection, mean quantity was 4.9 log₁₀ copies/mL for those <1 year, 4.7 log₁₀ copies/mL among those 1-9 years, and 4.6 log₁₀ copies/mL among those ≥10 years since first episode. CONCLUSIONS Rates of total and subclinical HSV-2 shedding decrease after the first year following the initial clinical episode. However, viral shedding persists at high rates and copy numbers years after infection, and therefore may pose continued risk of HSV-2 transmission to sexual partners.

Contribution of HIV infection to mortality among cancer patients in Uganda

Objective:HIV infection is associated with cancer risk. This relationship has resulted in a growing cancer burden, especially in resource-limited countries where HIV is highly prevalent. Little is known, however, about how HIV affects cancer survival in these settings. We therefore investigated the role of HIV in cancer survival in Uganda. Design:Retrospective cohort (N = 802). Methods:Eligible cancer patients were residents of Kyadondo County, at least 18 years of age at cancer diagnosis, and diagnosed between 2003 and 2010 with one of the following: breast cancer, cervical cancer, non-Hodgkins lymphoma, Hodgkins lymphoma, or esophageal cancer. Patients were classified as HIV-infected at cancer diagnosis based on a documented positive HIV antibody test, medical history indicating HIV infection, or an HIV clinic referral letter. The primary outcome, vital status at 1 year following cancer diagnosis, was abstracted from the medical record or determined through linkage to the national hospice database. The risk of death during the year after cancer diagnosis was compared between cancer patients with and without evidence of HIV infection using Cox proportional hazards regression. Results:HIV-infected cancer patients in Uganda experienced a more than two-fold increased risk of death during the year following cancer diagnosis compared to HIV-uninfected cancer patients [hazard ratio 2.28; 95% confidence interval (CI) 1.61–3.23]. This association between HIV and 1-year cancer survival was observed for both cancers with (hazard ratio 1.56; 95% CI 1.04–2.34) and without (hazard ratio 2.68; 95% CI 1.20–5.99) an infectious cause. Conclusion:This study demonstrates the role of HIV in cancer survival for both cancers with and without an infectious cause in a resource-limited, HIV-endemic setting.

Gender Differences in Clinical Presentation and Outcomes of Epidemic Kaposi Sarcoma in Uganda

Introduction The incidence of Kaposi sarcoma (KS) has increased dramatically among women in sub-Saharan Africa since the onset of the HIV pandemic, but data on KS disease in women are limited. To identify gender-related differences in KS presentation and outcomes, we evaluated the clinical manifestations and response in men and women with AIDS-associated KS in Uganda. Methods and Findings HIV-infected adults with KS attending the Infectious Diseases Institute (IDI) and Uganda Cancer Institute (UCI) in Kampala, Uganda between 2004 and 2006 were included in a retrospective cohort. Evaluation of KS presentation was based on the clinical features described at the initial KS visit. Response was evaluated as the time to “improvement”, as defined by any decrease in lesion size, lesion number, or edema. The cohort consisted of 197 adults with HIV and KS: 55% (108/197) were women. At presentation, the median CD4 T-cell count was significantly lower in women (58 cells/mm3; IQR 11–156 cells/mm3) than men (124 cells/mm3; IQR 22–254 cells/mm3) (p = 0.02). Women were more likely than men to present with lesions of the face (OR 2.8, 95% CI, 1.4, 5.7; p = 0.005) and hard palate (OR 2.0, 95% CI, 1.1, 3.7; p = 0.02), and were less likely than men to have lower extremity lesions (OR 0.54, 95% CI, 0.3, 0.99; p = 0.05). Women were less likely than men to demonstrate clinical improvement (HR = 0.52, CI 0.31, 0.88; p = 0.01) in multivariate analysis. Conclusions The clinical presentation and response of KS differs between men and women in Uganda. These data suggest that gender affects the pathophysiology of KS, which may have implications for the prevention, diagnosis, and treatment of KS in both men and women. Prospective studies are needed to identify predictors of response and evaluate efficacy of treatment in women with KS, particularly in Africa where the disease burden is greatest.

A Population-Level Evaluation of the Effect of Antiretroviral Therapy on Cancer Incidence in Kyadondo County, Uganda, 1999 – 2008

Background:The introduction of antiretroviral therapy (ART) in the United States and Europe has led to changes in the incidence of cancers among HIV-infected persons, including dramatic decreases in Kaposi sarcoma and non-Hodgkin lymphoma, and increases in Hodgkin lymphoma, liver, and anogenital malignancies. We sought to evaluate whether increasing availability of ART is associated with changing cancer incidence in Uganda. Methods:Incident cases of 10 malignancies were identified from Kampala Cancer Registry from 1999 to 2008. ART coverage rates for Uganda were abstracted from the Joint United Nations Program on HIV/AIDS reports. Negative binomial and Poisson regression modeled the association between ART coverage and age-adjusted cancer incidence. Results:ART coverage in Uganda increased from 0% to 43% from 1999 to 2008. With each 10% increase in ART coverage, incidence of Kaposi sarcoma decreased by 5% [incidence rate ratio (IRR) = 0.95, 95% confidence interval: 0.91 to 0.99, P = 0.02] and stomach cancer decreased by 13% [IRR = 0.87 (95% CI: 0.80 to 0.95), P = 0.002]. Conversely, incidence of non-Hodgkin lymphoma increased by 6% [IRR = 1.06 (95% CI: 1 to 1.12), P = 0.05], liver cancer by 12% [IRR = 1.12 (95% CI: 1.04 to 1.21), P = 0.002], prostate cancer by 5% [IRR = 1.05 (95% CI: 1 to 1.10), P = 0.05], and breast cancer by 5% [IRR = 1.05 (95% CI: 1 to 1.11), P = 0.05]. ART coverage was not associated with incidence of invasive cervical cancer, lung, colon, and Hodgkin disease. These findings were similar when restricted to histologically confirmed cases. Conclusions:Our findings suggest that AIDS-defining malignancies and other malignancies are likely to remain significant public health burdens in sub-Saharan Africa even as ART availability increases.

Challenges in the detection, prevention, and treatment of HIV-associated malignancies in low- and middle-income countries in Africa.

Abstract:Cancers associated with immunosuppression and infections have long been recognized as a major complication of HIV/AIDS. More recently, persons living with HIV are increasingly diagnosed with a wider spectrum of HIV-associated malignancies (HIVAM) as they live longer on combination antiretroviral therapy. This has spurred research to characterize the epidemiology and determine the optimal management of HIVAM with a focus on low-and middle-income countries (LMICs). Given background coinfections, environmental exposures, host genetic profiles, antiretroviral therapy usage, and varying capacities for early diagnosis and treatment, one can expect the biology of cancers in HIV-infected persons in LMICs to have a significant impact on chronic HIV care, as is now the case in high-income countries. Thus, new strategies must be developed to effectively prevent, diagnose, and treat HIVAM in LMICs; provide physical/clinical infrastructures; train the cancer and HIV workforce; and expand research capacity—particularly given the challenges posed by the limitations on available transportation and financial resources and the populations general rural concentration. Opportunities exist to extend resources supported by the Presidents Emergency Plan for AIDS Relief and the Global Fund to Fight AIDS, Tuberculosis, and Malaria to improve the health-care infrastructure and train the personnel required to prevent and manage cancers in persons living with HIV. These HIV chronic care infrastructures could also serve cancer patients regardless of their HIV status, facilitating long-term care and treatment for persons who do not live near cancer centers, so that they receive the same degree of care as those receiving chronic HIV care today.

Oral HHV-8 Replication Among Women in Mombasa, Kenya

Human herpesvirus‐8 (HHV‐8) replication in the oropharynx may play an important role in HHV‐8 transmission and contribute to the development of Kaposi sarcoma (KS) in some individuals. Studies in the United States and Europe report high rates of HHV‐8 DNA detection in saliva of HHV‐8 infected men, but little is known about the natural history of HHV‐8 among persons in sub‐Saharan Africa, where prevalence of HHV‐8 infection and KS is greatest. To address this gap, this study evaluated oral HHV‐8 replication in a cohort of 40 HHV‐8 seropositive Kenyan women. Study clinicians collected daily oral swabs from participants for up to 30 consecutive days, and swab samples were tested for HHV‐8 DNA using quantitative, real‐time polymerase chain reaction. HHV‐8 was detected at least once in 27 (68%) participants, and the overall shedding rate was 23%. On days with HHV‐8 detection, mean HHV‐8 quantity was 4.5 log10 copies/ml. Among HIV‐infected women, CD4 count ≥500 cells/mm3 versus <500 cells/mm3 was associated with higher HHV‐8 copy number (4.8 log10 copies/ml vs. 3.4 log10 copies/ml; coef 1.2 [95% CI, 0.5–1.9]; P = 0.001) and a higher HHV‐8 shedding rate (49% vs.12%; RR, 4.2 [95% CI, 0.8–21.4]; P = 0.08). No other factors were associated with HHV‐8 shedding rate or copy number. The study demonstrates high rates and quantity of HHV‐8 in the oropharynx of HHV‐8 seropositive African women. These findings support the observation that oral replication is an essential feature of HHV‐8 infection, with likely implications for HHV‐8 transmission and KS pathogenesis. J. Med. Virol. 86: 1759–1765, 2014.

Genital Herpes Simplex Virus Type 2 Shedding Among Adults With and Without HIV Infection in Uganda.

BACKGROUND Despite the high prevalence of herpes simplex virus type 2 (HSV-2) in sub-Saharan Africa, the natural history of infection among Africans is not well characterized. We evaluated the frequency of genital HSV shedding in HIV-seropositive and HIV-seronegative men and women in Uganda. METHODS Ninety-three HSV-2-seropositive Ugandan adults collected anogenital swab specimens for HSV DNA quantification by polymerase chain reaction 3 times daily for 6 weeks. RESULTS HSV-2 was detected from 2484 of 11 283 swab specimens collected (22%), with a median quantity of 4.3 log10 HSV copies/mL (range, 2.2-8.9 log10 HSV copies/mL). Genital lesions were reported on 749 of 3875 days (19%), and subclinical HSV shedding was detected from 1480 of 9113 swab specimens (16%) collected on days without lesions. Men had higher rates of total HSV shedding (relative risk [RR], 2.0 [95% confidence interval {CI}, 1.3-2.9]; P < .001); subclinical shedding (RR, 1.7 [95% CI, 1.1-2.7]; P = .01), and genital lesions (RR, 2.1 [95% CI, 1.2-3.4]; P = .005), compared with women. No differences in shedding rates or lesion frequency were observed based on HIV serostatus. CONCLUSIONS HSV-2 shedding frequency and quantity are high among HSV-2-seropositive adults in sub-Saharan Africa, including persons with and those without HIV infection. Shedding rates were particularly high among men, which may contribute to the high prevalence of HSV-2 and early acquisition among African women.

Stage-Stratified Approach to AIDS-Related Kaposi's Sarcoma: Implications for Resource-Limited Environments

In an accompanying editorial, Krell and Stebbing 2 recommended that the same stage-stratified approach, yielding good outcomeswhenappliedasa(nonrandomized)strategyatasinglesiteina high-resource setting, be adopted globally, and that if cost and chemotherapy-related infrastructural barriers could be overcome, pegylated liposomal doxorubicin should be made available for all patients with advanced-stage KS in sub-Saharan Africa (SSA), where the world’s burden of HIV-associated KS is concentrated. As investigatorsinvolvedinstudyingHIV-associatedKSinSSA,webelievethat morecomplexissuesmustberigorouslyaddressedbeforerecommendations for optimal treatment in this setting can be made. The editorial 2 does not consider significant differences between patientsinresource-richandresource-limitedsettingsthatmayinflu

Hepatitis B incidence and prevention with antiretroviral therapy among HIV positive individuals in Rakai, Uganda.

Objective: Antiretroviral therapy (ART) may interfere with replication of hepatitis B virus (HBV), raising the hypothesis that HBV infection might be prevented by ART. We investigated the incidence and risk factors associated with HBV among HIV-infected adults in Rakai, Uganda. Methods: We screened stored sera from 944 HIV-infected adults enrolled in the Rakai Community Cohort Study between September 2003 and March 2015 for evidence of HBV exposure. Serum from participants who tested anti-hepatitis B core-negative (497) at baseline were tested over 3–7 consecutive survey rounds for incident HBV. Poisson incidence methods were used to estimate incidence of HBV with 95% confidence intervals (CIs), whereas Cox proportional regression methods were used to estimate hazard ratios (HRs). Results: Thirty-nine HBV infections occurred over 3342 person-years, incidence 1.17/100 person-years. HBV incidence was significantly lower with ART use: 0.49/100 person-years with ART and 2.3/100 person-years without ART [adjusted HR (aHR) 0.25, 95% CI 0.1–0.5, P < 0.001], and with lamivudine (3TC) use: 0.58/100 person-years) with 3TC and 2.25/100 person-years without 3TC (aHR 0.32, 95% CI 0.1–0.7, P =  < 0.007). No new HBV infections occurred among those on tenofovir-based ART. HBV incidence also decreased with HIV RNA suppression: 0.6/100 person-years with 400 copies/ml or less and 4.0/100 person-years with more than 400 copies/ml (aHR, 6.4, 95% CI 2.2–19.0, P < 0.001); and with age: 15–29 years versus 40–50 years (aHR 3.2, 95% CI 1.2–9.0); 30–39 years versus 40–50 years (aHR 2.1, 95% CI 0.9–5.3). Conclusion: HBV continues to be acquired in adulthood among HIV-positive Ugandans and HBV incidence is dramatically reduced with HBV-active ART. In addition to widespread vaccination, initiation of ART may prevent HBV acquisition among HIV-positive adults in sub-Saharan Africa.