Suzanne P. Fiorillo

Immune reconstitution inflammatory syndrome associated with Kaposi sarcoma: higher incidence and mortality in Africa than in the UK.

Objectives:To assess the incidence, predictors, and outcomes of Kaposi sarcoma-associated paradoxical immune reconstitution inflammatory syndrome (KS-IRIS) in antiretroviral therapy (ART)-naive HIV-infected patients with Kaposi sarcoma initiating ART in both well resourced and limited-resourced settings. Design:Pooled analysis of three prospective cohorts of ART-naive HIV-infected patients with Kaposi sarcoma from sub-Saharan Africa (SSA) and one from the UK. Methods:KS-IRIS case definition was standardized across sites. Cox regression and Kaplan–Meier survival analysis were used to identify the incidence and predictors of KS-IRIS and Kaposi sarcoma-associated mortality. Results:Fifty-eight of 417 (13.9%) eligible individuals experienced KS-IRIS with an incidence 2.5 times higher in the African vs. European cohorts (P = 0.001). ART alone as initial Kaposi sarcoma treatment (hazard ratio 2.97, 95% confidence interval (CI) 1.02–8.69); T1 Kaposi sarcoma stage (hazard ratio 2.96, 95% CI 1.26–6.94); and plasma HIV-1 RNA more than 5 log10 copies/ml (hazard ratio 2.14, 95% CI 1.25–3.67) independently predicted KS-IRIS at baseline. Detectable plasma Kaposi sarcoma-associated herpes virus (KSHV) DNA additionally predicted KS-IRIS among the 259 patients with KSHV DNA assessed (hazard ratio 2.98, 95% CI 1.23–7.19). Nineteen KS-IRIS patients died, all in SSA. Kaposi sarcoma mortality was 3.3-fold higher in Africa, and was predicted by KS-IRIS (hazard ratio 19.24, CI 7.62–48.58), lack of chemotherapy (hazard ratio 2.35, 95% CI 1.09–5.05), pre-ART CD4 cell count less than 200 cells/&mgr;l (hazard ratio 2.04, 95% CI 0.99–4.2), and detectable baseline KSHV DNA (hazard ratio 2.12, 95% CI 0.94–4.77). Conclusion:KS-IRIS incidence and mortality are higher in SSA than in the UK. This is largely explained by the more advanced Kaposi sarcoma disease and lower chemotherapy availability. KS-IRIS is a major contributor to Kaposi sarcoma-associated mortality in Africa. Our results support the need to increase awareness on KS-IRIS, encourage earlier presentation, referral and diagnosis of Kaposi sarcoma, and advocate on access to systemic chemotherapy in Africa.

Evaluation of Plasma Human Herpesvirus 8 DNA as a Marker of Clinical Outcomes during Antiretroviral Therapy for AIDS-Related Kaposi Sarcoma in Zimbabwe

BACKGROUND The usefulness of plasma human herpesvirus 8 (HHV-8) DNA as a marker of response to treatment for acquired immunodeficiency syndrome-associated Kaposi sarcoma (AIDS-KS) in an African setting is unknown. METHODS We conducted a prospective pilot study at the Parirenyatwa Hospital Kaposi Sarcoma Clinic (Harare, Zimbabwe) to investigate the hypothesis that the clinical response of AIDS-KS is associated with suppression of HHV-8 DNA. Antiretroviral therapy (ART) was provided as coformulation of abacavir, lamivudine, and zidovudine. Clinical response was defined as survival to week 96 with either complete or partial resolution of KS disease. RESULTS Ninety ART-naive participants (62 men and 28 women) aged >18 years who had human immunodeficiency virus type 1 (HIV-1) infection and biopsy-confirmed KS were studied; 82% had stage T1 disease. Fifty participants received adjunctive chemotherapy. The median CD4(+) lymphocyte count increased from 124 cells/microL at baseline to 281 cells/microL, the plasma HIV-1 RNA level decreased from 4.69 to <2.60 log(10) copies/mL, the plasma HHV-8 DNA level decreased from 660 to <25 copies/mL, and HHV-8 DNA level in peripheral blood mononuclear cells decreased from 2790 to 37 copies/10(6) cells (P < .001 for each comparison). There were 14 deaths (16%) and 13 patients (15%) lost to follow-up. The most common cause of death was infection. Clinical response of KS occurred in 17 participants (19%). Pretreatment plasma HHV-8 DNA levels of <660 copies/mL were associated with greater survival (odds ratio, 2.83; 95% confidence interval, 1.07-7.53; P = .04) and a better clinical response (odds ratio, 6.38; 95% confidence interval, 1.68-24.19; P = .006). CONCLUSIONS AIDS-KS tumor responses after ART initiation were limited. Pretreatment plasma HHV-8 DNA level may be a surrogate for KS disease that is in need of intensive clinical management.

Lack of evidence for frequent heterosexual transmission of human herpesvirus 8 in Zimbabwe.

BACKGROUND There is conflicting evidence about the contribution of heterosexual transmission to the spread of human herpesvirus 8 (HHV-8) in southern Africa. This study evaluated the hypothesis that HHV-8 infection is associated with risk factors for human immunodeficiency virus type 1 (HIV-1) and other sexually transmitted infections among Zimbabwean men. METHODS HHV-8 seroprevalence was determined for 2750 participants in the Zimbabwe AIDS Prevention Project cohort of male factory workers in Harare, Zimbabwe. Potential associations of HHV-8 antibody detection with risk factors for HIV-1 infection were examined by univariate analysis. Variables with P < .1 in the univariate analysis were included in a multivariate logistic regression model. HHV-8 seroprevalence was also determined among 297 heterosexual couples. RESULTS Prevalence of HHV-8, HIV-1, and HHV-8 and HIV-1 coinfection was 28.5% (95% confidence interval [CI], 26.8%-30.2%), 19.5% (95% CI, 18.0%-20.9%), and 6.5% (95% CI, 5.6%-7.5%), respectively. Detection of HHV-8 antibodies was independently associated with older age and HIV-1 infection but not with number of recent sex partners, marital status, education, condom use, prior sexually transmitted infections, payment for sex, chronic hepatitis B infection, or incident HIV-1 infection. HHV-8 seroprevalence was 31.7% (95% CI, 26.3-37.0) among wives in the couples tested, but HHV-8 infection of wives was not associated with HHV-8 infection of husbands (odds ratio, 1.08; 95% CI, 0.62-1.88; P = .8). CONCLUSIONS HHV-8 and HIV-1 infection did not have common sexual risk factors among urban Zimbabwean men. Sexual transmission does not explain the high prevalence of HHV-8 in this population.

Seroprevalence of Hepatitis B and C Viruses Among Children in Kilimanjaro Region, Tanzania

BACKGROUND Data on human immunodeficiency virus (HIV) and hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection among children in Africa are limited. We evaluated the seroprevalence of both viruses among healthy, HIV-uninfected children and HIV-infected children in the Kilimanjaro region of northern Tanzania. METHODS HBV and HCV markers were assessed using serum and plasma samples from HIV-negative children ages 1 month to 18 years, recruited primarily from 2 hospital vaccination clinics; and HIV-infected children 1-16 years of age, enrolled in care and on highly active antiretroviral therapy (HAART). HBV markers included hepatitis B surface antigen (HBsAg), hepatitis B surface antibody, and hepatitis B core antibody (HBcAb). Evidence of any prior HBV infection was defined as a single positive HBsAg or HBcAb result; presumed chronic hepatitis B infection was defined as a single positive HBsAg result. HCV infection was assessed by anti-HCV enzyme-linked immunosorbent assay. RESULTS Samples from 547 children were tested. Of 157 children infected with HIV, 9.6% (95% CI: 4.9, 14.2) showed evidence of any HBV infection, compared to 2.1% (95% CI: .6, 3.5) of HIV-negative children. Children with HIV were much more likely to show evidence of HBV infection than children without HIV (odds ratio [OR] = 5.0, P < .0001). Prevalence of presumed chronic HBV infection was 2.9% (95% CI: 1.5, 4.3) overall. Again, prevalence was higher among HIV-infected children (7.0% [95% CI: 3.0, 11.0]) compared to HIV-negative children (1.3% [95% CI: .2, 2.4]; OR = 5.8 [P = .0003]). Of 546 samples tested for anti-HCV antibody, none were positive. CONCLUSION HBV seroprevalence is high among children in the Kilimanjaro Region, with a significantly higher prevalence among children who are infected with HIV. Routine screening for HBV is needed among HIV-infected children. Patients with coinfection require closer monitoring of liver transaminases due to potential for hepatic toxicities, and they may need HAART regimens that will target both viruses. Guidelines for the management of coinfected children are urgently needed.

Changes in HIV risk behavior and seroincidence among clients presenting for repeat HIV counseling and testing in Moshi, Tanzania

Abstract While HIV counseling and testing (HCT) has been considered an HIV preventive measure in Africa, data are limited describing behavior changes following HCT. This study evaluated behavior changes and estimated HIV seroincidence rate among returning HCT clients. Repeat and one-time testing clients receiving HCT services in Moshi, Tanzania were identified. Information about sociodemographic characteristics, HIV-related behaviors and testing reasons were collected, along with HIV serostatus. Six thousand seven hundred and twenty-seven clients presented at least once for HCT; 1235 (18.4%) were HIV seropositive, median age was 29.7 years and 3712 (55.3%) were women. 1382 repeat and 4272 one-time testers were identified. Repeat testers were more likely to be male, older, married, or widowed, and testing because of unfaithful partner or new sexual partner. One-time testers were more likely to be students and testing due to illness. At second test, repeat testers were more likely to report that partners had received HIV testing, not have concurrent partners, not suspect partners have HIV, and have partners who did not have other partners. Clients who intended to change behaviors after the first test were more likely to report having changed behaviors by remaining abstinent (OR 2.58; p<0.0001) or using condoms (OR 2.00; p=0.006) at the second test. HIV seroincidence rate was 1.49 cases/100 person-years (PY). Clients presenting for repeat HCT reported some reduction of risky behavior and improved knowledge of sexual practices and HIV serostatus of their partners. Promoting behavior change through HCT should continue to be a focus of HIV prevention efforts in sub-Saharan Africa.

Attitudes and barriers towards pre-exposure prophylaxis (PrEP) among high-risk HIV-seronegative men who have sex with men.

Objective: Recent studies have demonstrated the efficacy of antiretroviral preexposure prophylaxis (PrEP) for prevention of HIV-1 infection. The purpose of this study was to identify barriers to PrEP use among high HIV-risk men who have sex with men in Denver, Colorado. Methods: A 19 question Likert-scale survey was used to assess knowledge of PrEP; attitudes towards cost, side effects, and alternative prevention methods; and the effects of PrEP on sexual behaviors and practices. The survey was administered at study entry and six months later to HIV seronegative, men who have sex with men and male-tofemale transgendered women who have sex with men and participate in high-risk sexual behavior. Results: Between June and September 2013, 65 participants from the metropolitan Denver area completed the survey. Median age was 36 years (range; 20-52 years); 88% were white, 6% Hispanic, and 1.5% African American; 65% had at least a college degree or higher and 27% had more than high school education. The reported number of sexual partners in the past six months ranged from zero to 150 partners (median 3 partners) and 75% reported condom use during all sexual encounters. Although 72.3% reported prior knowledge of PrEP only five participants (7.7%) reported ever using PrEP in the past. Participants were most likely (93.8%) to use PrEP in the future if they were in a monogamous relationship with an HIV-infected partner and least likely to use PrEP if it required out-of-pocket costs (10.7%). Younger age was associated with decreased odds of future PrEP use even if PrEP was provided free of charge (OR 0.2, 95% CI 0.1, 1.0). Higher number of sexual partners in the preceding six months was associated with decreased odds of using condoms if taking PrEP in the future (aOR 0.2; 95% CI 0.1, 0.8). No changes in survey responses were noted between baseline and six months. Conclusions: PrEP usage was uncommon among men at high risk for sexual acquisition of HIV infection and cost of antiretroviral drugs was a major barrier to future PrEP use. If PrEP is to have major impact on transmission of HIV-1, expanded efforts to decrease cost and increase community awareness of PrEP safety and efficacy are needed.

Establishment of biochemistry reference values for healthy Tanzanian infants, children and adolescents in Kilimanjaro Region.

To establish common biochemistry reference intervals for Tanzanian infants, children and adolescents living in the Kilimanjaro Region.

Chest radiography for predicting the cause of febrile illness among inpatients in Moshi, Tanzania.

AIM To describe chest radiographic abnormalities and assess their usefulness for predicting causes of fever in a resource-limited setting. MATERIALS AND METHODS Febrile patients were enrolled in Moshi, Tanzania, and chest radiographs were evaluated by radiologists in Tanzania and the United States. Radiologists were blinded to the results of extensive laboratory evaluations to determine the cause of fever. RESULTS Of 870 febrile patients, 515 (59.2%) had a chest radiograph available; including 268 (66.5%) of the adolescents and adults, the remainder were infants and children. One hundred and nineteen (44.4%) adults and 51 (20.6%) children were human immunodeficiency virus (HIV)-infected. Among adults, radiographic abnormalities were present in 139 (51.9%), including 77 (28.7%) with homogeneous and heterogeneous lung opacities, 26 (9.7%) with lung nodules, 25 (9.3%) with pleural effusion, 23 (8.6%) with cardiomegaly, and 13 (4.9%) with lymphadenopathy. Among children, radiographic abnormalities were present in 87 (35.2%), including 76 (30.8%) with homogeneous and heterogeneous lung opacities and six (2.4%) with lymphadenopathy. Among adolescents and adults, the presence of opacities was predictive of Streptococcus pneumoniae and Coxiella burnetii, whereas the presence of pulmonary nodules was predictive of Histoplasma capsulatum and Cryptococcus neoformans. CONCLUSIONS Chest radiograph abnormalities among febrile inpatients are common in northern Tanzania. Chest radiography is a useful adjunct for establishing an aetiologic diagnosis of febrile illness and may provide useful information for patient management, in particular for pneumococcal disease, Q fever, and fungal infections.

Relationship of vitamin D insufficiency to AIDS-associated Kaposi's sarcoma outcomes: retrospective analysis of a prospective clinical trial in Zimbabwe

OBJECTIVES The prevalence of vitamin D insufficiency in Africans with AIDS-associated Kaposi sarcoma (AIDS-KS) and the role of vitamin D in AIDS-KS progression are unknown. We hypothesized that a high prevalence of vitamin D deficiency would be found in Zimbabweans with AIDS-KS and that low baseline vitamin D would correlate with progression of AIDS-KS. METHODS Ninety subjects were enrolled in a prospective pilot study investigation of the effect of antiretroviral therapy in the treatment of AIDS-KS in Harare, Zimbabwe. Co-formulated abacavir, lamivudine, and zidovudine was initiated; chemotherapy was provided at the discretion of the provider. Participants were followed for 96 weeks. 25-Hydroxyvitamin D was measured in stored specimens collected at study entry. The relationship between vitamin D and clinical response was described by odds ratio and 95% confidence interval. RESULTS Samples were available for 85 participants; 45 (53%) subjects had inadequate (<75 nmol/l) 25-hydroxyvitamin D. HIV-1 RNA was significantly higher among those with insufficient vitamin D (4.7 vs. 4.5 log, p = 0.04). Tumor response, survival, and KS-IRIS were not associated with vitamin D (p ≥ 0.3). CONCLUSIONS Vitamin D insufficiency was common among Zimbabweans with AIDS-KS but not associated with outcomes after initiation of antiretroviral therapy.

Rapid Multiplexed Immunoassay for Detection of Antibodies to Kaposi's Sarcoma-Associated Herpesvirus.

Diagnosis of KSHV-infected individuals remains a challenge. KSHV prevalence is high in several populations with high prevalence of HIV, leading to increased risk of development of Kaposi’s sarcoma (KS). While current assays are reliable for detecting antibodies to KSHV, none are routinely utilized to identify individuals with KSHV infection and thus at increased risk for KS due to assay complexity, lack of access to testing, and cost, particularly in resource-limited settings. Here we describe the addition of KSHV proteins LANA and K8.1 to a previously evaluated HIV/co-infection multiplexed fluorescence immunoassay system. This study demonstrates assay performance by measuring antibody reactivity for KSHV and HIV-1 in a collection of clinical specimens from patients with biopsy-proven KS and sourced negative controls. The KSHV assay correctly identified 155 of 164 plasma samples from patients with biopsy-proven KS and 85 of 93 KSHV antibody (Ab)-negative samples for a sensitivity of 95.1% and specificity of 91.4%. Assay performance for HIV-1 detection was also assessed with 100% agreement with independently verified HIV-1 Ab-positive and Ab-negative samples. These results demonstrate good sensitivity and specificity for detection of antibody to KSHV antigens, and demonstrate the potential for multiplexed co-infection testing in resource-limited settings to identify those at increased risk for HIV-1-related complications.