The epidemiology of Kaposi’s sarcoma associated-herpesvirus in Uganda

Over the past two decades there has been an explosion in the number of cases of Kaposi’s sarcoma (KS) in parts of sub-Saharan Africa, where Kaposi’s sarcoma associated-herpesvirus (KSHV) and HIV are relatively prevalent. Currently KS is the most commonly reported cancer in Uganda causing significant morbidity and mortality. Limiting KSHV transmission or halting disease progression could prevent KS. Here, I describe an investigation of factors that might impact on transmission of KSHV and report the first prospective study of antibody titre to KSHV to determine risk of KS from Africa. Stored samples from Medical Research Council, Uganda cohorts were tested using an ELISA to KSHV antigens. Results from a birth cohort found that among both mothers and children malaria parasitaemia was identified as a novel association with KSHV seropositivity. Among children HIV exposure and HIV infection was associated with antibodies to KSHV. A random effects meta-analysis conducted to clarify wider evidence of an association between KSHV and HIV found that HIV was associated with an increased prevalence of antibodies to KSHV in mothers and children. A case-control study nested within a longitudinal HIV cohort found among individuals who develop KS, antibody titres to KSHV are higher and increased over time compared to adults who did not. It is plausible that control of malaria may also reduce the spread of KSHV. How malaria may interact with KSHV and if malaria control will reduce transmission are key future questions. Prevention and treatment of HIV with anti-retroviral therapy may lower KSHV transmission between mothers and children. For individuals with HIV-KSHV co-infection, increasing antibody titre to KSHV precedes development of KS. Research is required to elucidate co-factors driving progression to cancer. A clinically valid tool to screen for risk of HIV-associated KS is urgently needed

Association between malaria exposure and Kaposi's sarcoma-associated herpes virus seropositivity in Uganda.

OBJECTIVE: Unlike other herpes viruses, Kaposi's sarcoma-associated herpes virus (KSHV) is not ubiquitous worldwide and is most prevalent in sub-Saharan Africa. The reasons for this are unclear. As part of a wider investigation of factors that facilitate transmission in Uganda, a high prevalence country, we examined the association between antimalaria antibodies and seropositivity against KSHV. METHODS: Antibodies against P. falciparum merozoite surface protein (PfMSP)-1, P. falciparum apical membrane antigen (PfAMA)-1 and KSHV antigens (ORF73 and K8.1) were measured in samples from 1164 mothers and 1227 children. RESULTS: Kaposi's sarcoma-associated herpes virus seroprevalence was 69% among mothers and 15% children. Among mothers, KSHV seroprevalence increased with malaria antibody titres: from 60% to 82% and from 54% to 77%, comparing those with the lowest and highest titres for PfMSP-1 and PfAMA-1, respectively (P < 0.0001). Among children, only antibodies to PfAMA-1 were significantly associated with KSHV seropositivity, (P < 0.0001). In both mothers and children, anti-ORF73 antibodies were more strongly associated with malaria antibodies than anti-K8.1 antibodies. CONCLUSION: The association between malaria exposure and KSHV seropositivity suggests that malaria is a cofactor for KSHV infection or reactivation

Trends in Kaposi's sarcoma-associated Herpesvirus antibodies prior to the development of HIV-associated Kaposi's sarcoma: a nested case-control study

HIV-associated Kaposi's sarcoma (KS) is a public health challenge in sub-Saharan Africa since both the causative agent, Kaposi's sarcoma associated-herpesvirus (KSHV), and the major risk factor, HIV, are prevalent. In a nested case-control study within a long-standing clinical cohort in rural Uganda, we used stored sera to examine the evolution of antibody titres against the KSHV antigens K8.1 and latency-associated nuclear antigen (LANA) among 30 HIV-infected subjects who subsequently developed HIV-related KS (cases) and among 108 matched HIV/KSHV coinfected controls who did not develop KS. Throughout the 6 years prior to diagnosis, antibody titres to K8.1 and LANA were significantly higher among cases than controls (p &#60; 0.0001), and titres increased prior to diagnosis in the cases. K8.1 titres differed more between KS cases and controls, compared to LANA titres. These differences in titre between cases and controls suggest a role for lytic viral replication in the pathogenesis of HIV-related KS in this setting

The impact of antiretroviral therapy on symptom burden among HIV outpatients with low CD4 count in rural Uganda: nested longitudinal cohort study.

BACKGROUND: Individuals with HIV have a high prevalence of physical and psychological symptoms throughout their disease course. Despite the clinical and public health implications of unresolved pain and symptoms, little is known about the effect of anti-retroviral therapy (ART) on these outcomes. This study aimed to assess the impact on symptom burden for the year after ART initiation in individuals with a CD4 count <200 cells/uL in Uganda. METHODS: HIV-infected, ART-naıve adults referred from voluntary testing and counseling services in rural Uganda for enrollment into a randomized controlled trial to test fluconazole as primary prophylaxis against cryptococcal disease were invited to complete the Memorial Symptom Assessment Scale-Short Form (MSAS-SF) prior to commencing ART and at two subsequent follow up visits. This tool measures self-reported 7-day period prevalence and associated burden of physical and psychological symptoms. Changes in the total number of symptoms and distress indices with time on ART and trial arm were investigated through fitting Linear Mixed Models for repeated measures. RESULTS: During the first year of ART initiation the prevalence of most individual symptoms remained constant. The notable exceptions which improved after commencing ART are as follow; prevalence of pain (prevalence changed from 79% to 60%), weight loss (67% to 31%), lack of appetite (46% to 28%), feeling sad (52% to 25%) and difficulty sleeping (35% to 23%). The total number of symptoms and distress indices reduced after treatment commenced. Of concern was that half or more study participants remained with symptoms of pain (60%), itching (57%), skin changes (53%) and numbness in hands and feet (52%) after starting ART. Sixteen symptoms remained with a burden of 25% or more. CONCLUSION: Despite the beneficial effect of ART on reducing symptoms, some patients continue to experience a high symptom burden. It is essential that HIV services in sub-Saharan Africa integrate management of symptoms into their programmes. TRIAL REGISTRATION: CRYPTOPRO [ISRCTN 76481529 ], November 2004

Trends in Kaposi's sarcoma-associated Herpesvirus antibodies prior to the development of HIV-associated Kaposi's sarcoma: a nested case-control study.

HIV-associated Kaposi's sarcoma (KS) is a public health challenge in sub-Saharan Africa since both the causative agent, Kaposi's sarcoma associated-herpesvirus (KSHV), and the major risk factor, HIV, are prevalent. In a nested case-control study within a long-standing clinical cohort in rural Uganda, we used stored sera to examine the evolution of antibody titres against the KSHV antigens K8.1 and latency-associated nuclear antigen (LANA) among 30 HIV-infected subjects who subsequently developed HIV-related KS (cases) and among 108 matched HIV/KSHV coinfected controls who did not develop KS. Throughout the 6 years prior to diagnosis, antibody titres to K8.1 and LANA were significantly higher among cases than controls (p < 0.0001), and titres increased prior to diagnosis in the cases. K8.1 titres differed more between KS cases and controls, compared to LANA titres. These differences in titre between cases and controls suggest a role for lytic viral replication in the pathogenesis of HIV-related KS in this setting

Co-administration of fluconazole increases nevirapine concentrations in HIV-infected Ugandans.

BACKGROUND: Data from retrospective studies have suggested that there may be an interaction between fluconazole and nevirapine, increasing nevirapine concentrations and potentially leading to hepatotoxicity. METHODS: This study was nested within a large double-blind placebo-controlled study designed to determine if primary prophylaxis with fluconazole (200 mg three times per week) could reduce cryptococcal disease [CRYPTOPRO (ISRCTN 76481529)] in HIV-infected adults in rural south-western Uganda. Detailed pharmacokinetic studies were performed on 49 participants (22 on placebo and 27 on fluconazole) who had been on fluconazole or placebo with nevirapine for > or =4 weeks. RESULTS: The geometric mean pre-dose concentrations of nevirapine were 3865 ng/mL [95% confidence interval (95% CI) 3452-4758 ng/mL] and 5141 ng/mL (95% CI 4760-6595 ng/mL) (P = 0.009) in the placebo and fluconazole arms, respectively. The change in the peak nevirapine concentration in plasma (C(max)) was also higher in the fluconazole arm compared with the placebo arm [median 6546 (95% CI 6040-7974) versus 5126 (95% CI 4739-5773) ng/mL, P = 0.012]. Fluconazole increased the nevirapine area under the curve (AUC) from 0 to 8 h by 29% [geometric mean AUC(0-8) 46 135 (95% CI 42 432-57 173) versus 35 871 (95% CI 32 808-41 372) ng.h/mL, P = 0.016]. In the larger cohort from which the participants were drawn, co-administration of fluconazole did not increase the risk of hepatotoxicity. CONCLUSIONS: Fluconazole led to significant increases in nevirapine exposure, but was not associated with evidence of increased hepatotoxicity

Kaposi’s sarcoma associated herpesvirus in a rural Ugandan cohort: 1992-2008

Background The prevalence and titres of antibodies against Kaposi’s sarcoma associated herpesvirus (KSHV) in rural Africa are not completely understood, nor are their trends over time in populations in which HIV is also endemic. We examined prevalence, titres, temporal trends and determinants of anti KSHV antibodies in each of three time periods (1990-91, 1999-2000 and 2007-2008) within a long-standing, rural population-based cohort in southwestern Uganda. Methods For each period, we measured antibodies to the K8.1 and ORF73 KSHV antigens in ~ 3000 people of all ages (1:1 sex ratio). Results In all periods, KSHV prevalence increased rapidly through childhood to ~ 90% by age 15 years, plateauing at ~ 95% thereafter. Similarly, antibody titres, particularly against the lytic antigen K8.1, were amongst the highest seen and increased significantly with age, suggesting sustained viral replication in this population. Male sex was also independently associated with higher prevalence, whereas HIV co-infection was not. A modest reduction in prevalence among children was noted in the most recent period. Discussion KSHV seroprevalence and antibodies titres in this rural Ugandan population are the highest yet reported, perhaps reflecting frequent viral reactivation and persistently elevated transmission

Early adoption of innovation in HPV prevention strategies: closing the gap in cervical cancer.

Cervical cancer (CC) is one of the highest prevailing causes of female cancer-related mortality globally. A significant discrepancy in incidence has been noted between high and low-middle-income countries. The origins of CC have been accredited to the human papillomavirus (HPV) with serotypes 16 and 18 being the most prevalent. HPV vaccines, with 90%-97% efficacy, have proven safe and currently function as the primary prevention method. In addition, secondary prevention by timely screening can potentially increase the 5-year survival rate by >90%. High-precision HPV DNA testing has proven to be both highly sensitive and specific for early detection and is advocated by the WHO. Lack of public awareness, poor screening infrastructure and access to vaccines, socio-cultural concerns, along with economic, workforce-associated barriers and the presence of marginalised communities unable to access services have contributed to a continued high incidence. This article comprehensively analyses the efficacy, coverage, benefits and cost-effectiveness of CC vaccines and screening strategies including the transition from cytological screening to HPV self-sampling, while simultaneously exploring the real-world disparities in their feasibility. Furthermore, it calls for the implementation of population-based approaches that address the obstacles faced in approaching the WHO 2030 targets for CC elimination. [Abstract copyright: © the authors; licensee ecancermedicalscience.

Increased risk of HPV-associated genital cancers in men and women as a consequence of pre-invasive disease

To assess the excess risk of HPV‐associated cancer (HPVaC) in two at‐risk groups – women with a previous diagnosis of high grade cervical intraepithelial neoplasia (CIN3) and both men and women treated for non‐cervical pre‐invasive ano‐genital disease. All CIN3 cases diagnosed in 1989‐2015 in Scotland were extracted from the Scottish cancer registry (SMR06). All cases of pre‐invasive penile, anal, vulval, and vaginal disease diagnosed in 1990‐2015 were identified within the NHS pathology databases in the two largest NHS health boards in Scotland. Both were linked to SMR06 to extract subsequent incidence of HPVaC following the diagnosis of CIN3 or pre‐invasive disease. Standardised incidence ratios were calculated for the risk of acquiring HPVaC for the two at‐risk groups compared with the general Scottish population. Among 69714 females in Scotland diagnosed with CIN3 (890360.9 person‐years), 179 developed non‐cervical HPVaC. CIN3 cases were at 3.2‐fold (95% CI: 2.7 to 3.7) increased risk of developing non‐cervical HPVaC, compared to the general female population. Among 1235 patients diagnosed with non‐cervical pre‐invasive disease (9667.4 person‐years), 47 developed HPVaC. Individuals with non‐cervical pre‐invasive disease had a substantially increased risk of developing HPVaC ‐ 15.5‐fold (95% CI: 11.1 to 21.1) increased risk for females and 28‐fold (11.3 to 57.7) increased risk for males. We report a significant additional risk of HPV‐associated cancer in those have been diagnosed with pre‐invasive HPV‐associated lesions including but not confined to the cervix. Uncovering the natural history of pre‐invasive disease has potential for determining screening, prevention and treatment