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BackgroundNew strategies are needed to combat the high incidence of cervical cancer in resource-limited settings such as sub-Saharan Africa. Screening for high-risk human papillomavirus (hrHPV) DNA is sensitive for pre-cancer, but its lack of specificity results in substantial overtreatment in low resource settings where additional testing (e.g., colposcopy) is rarely available. Testing for hrHPV E6/E7 mRNA may enhance specificity, but little is known about its performance characteristics in resource-limited settings.MethodsIn a series of community health fairs in rural Uganda, women aged 25 to 49 years provided self-collected vaginal samples, which were tested for hrHPV (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68) E6/E7 mRNA with the Aptima® assay. Positive specimens underwent testing for HPV-16 and 18/45. After excluding pregnant women, all women testing positive for any hrHPV subsequently were offered cervical biopsy to determine pathology.ResultsA total of 1892 women provided a vaginal sample for hrHPV testing during 24 health fairs. The median age was 34 years, HIV prevalence was 10, and 95% had not been previously screened. Prevalence of any hrHPV E6/E7 mRNA was 21% (95% confidence interval (CI): 19 to 23%); the prevalence of HPV-16 was 2.6%, HPV-18/45 1.9%, and HPV 16 and 18/45 were jointly found in 0.1% of the study population. Younger age, pregnancy and HIV-positivity were independently associated with any hrHPV infection. Of the 255 evaluable cervical biopsies, the positive predictive value of detecting any hrHPV E6/E7 mRNA for presence of cervical intraepithelial neoplasia grade 2 or higher ("CIN 2+") was 8.2% (95% CI: 5.1 to 12%). The positive predictive value associated with detection of HPV-16 mRNA (15%) or HPV-18/45 mRNA (15%) was only slightly higher.ConclusionAmong community-based women in Uganda, the prevalence of any hrHPV E6/E7 mRNA in vaginal samples was high, but the prevalence of the most oncogenic HPV types (16, 18, or 45) was substantially lower. Positive predictive value of hrHPV mRNA-positivity for CIN 2+ was also low, including when restricting to HPV 16/18/45-positivity. The findings emphasize the need to identify more specific screening approaches for cervical cancer.

Abstract Background Malaria is one of the most serious infectious diseases in the world. The malaria burden is greatly affected by human immunity, and immune responses vary between populations. Genetic diversity in KIR and HLA-C genes, which are important in immunity to infectious diseases, is likely to play a role in this heterogeneity. Several studies have shown that KIR and HLA-C genes influence the immune response to viral infections, but few studies have examined the role of KIR and HLA-C in malaria infection, and these have used low-resolution genotyping. The aim of this study was to determine whether genetic variation in KIR and their HLA-C ligands differ in Ugandan populations with historically varied malaria transmission intensity using more comprehensive genotyping approaches. Methods High throughput multiplex quantitative real-time PCR method was used to genotype KIR genetic variants and copy number variation and a high-throughput real-time PCR method was developed to genotype HLA-C1 and C2 allotypes for 1344 participants, aged 6 months to 10 years, enrolled from Ugandan populations with historically high (Tororo District), medium (Jinja District) and low (Kanungu District) malaria transmission intensity. Results The prevalence of KIR3DS1, KIR2DL5, KIR2DS5, and KIR2DS1 genes was significantly lower in populations from Kanungu compared to Tororo (7.6 vs 13.2%: p = 0.006, 57.2 vs 66.4%: p = 0.005, 33.2 vs 46.6%: p

Abstract Background Deep venous thrombosis (DVT) and its major complication pulmonary embolism (PE) are collectively known as venous thromboembolism. In Uganda, the prevalence of DVT among HIV patients has not been previously published. The aim of the study was to determine the prevalence and sonographic features of lower limb deep venous thrombosis among HIV positive patients on anti-retroviral treatment (ART). Methods This was a cross sectional study in which HIV positive patients on ART were recruited from an out-patient HIV clinic at Mulago National Referral Hospital. Patients were randomly selected and enrolled until a sample size of 384 was reached. Study participants underwent compression and Doppler ultrasound studies of both lower limb deep veins using Medison Sonoacer7 ultrasound machine. Resuts We found a prevalence of DVT of 9.1% (35 of 384 participants) among HIV patients on ART. The prevalence of latent (asymptomatic) DVT was 2.3%. Among 35 patients with DVT, 42.8% had chronic DVT; 31.1% had acute DVT and the rest had latent DVT. Among the risk factors, the odds of occurrence of DVT among patients with prolonged immobility were 4.81 times as high as in those with no prolonged immobility (p = 0.023; OR = 4.81; 95% CI 1.25–18.62). Treatment with second line anti-retroviral therapy (ART) including protease inhibitors (PIs) was associated with higher odds of DVT occurrence compared with first line ART (p = 0.020; OR = 2.38; 95% CI 1.14–4.97). The odds of DVT occurrence in patients with a lower CD4 count (

Objective. To describe the clinical decisions taken for patients failing on treatment and possible implementation leakages within the monitoring cascade at a large urban HIV Centre in Kampala, Uganda. Methods. As per internal clinic guidelines, VL results >1,000 copies/ml are flagged by a quality assurance officer and sent to the requesting clinician. The clinician fills a “decision form” choosing: (1) refer for adherence counselling, (2) repeat VL after 3 months, and (3) switch to second line. We performed data extraction on a random sample of 100 patients with VL test >1,000 copies/ml between January and August 2015. For each patient, we described the action taken by the clinicians. Results. Of 6,438 patients with VL performed, 1,021 (16%) had >1,000 copies/ml. Of the 100 (10.1%) clinical files sampled, 61% were female, median age was 39 years (IQR: 32–47), 81% were on 1st-line ART, 19% on 2nd-line, median CD4 count was 249 cells/µL (IQR: 145–390), median log10 VL 4.42 (IQR: 3.98–4.92). Doctors’ decisions were; refer for adherence counseling 49%, repeat VL for 25%, and switch to second line for 24% patients. Forty-one percent were not managed according to the guidelines. Of these, 29 (70.7%) were still active in care, 7 were tracked [5 (12.2%) lost to program, 2 (4.9%) dead] and 5 patients were not tracked. Conclusion. Despite the implementation of internal systems to manage patients failing ART, we found substantial leakages in the monitoring “cascade”. Additional measures and stronger clinical supervision are needed to make every test count, and to ensure appropriate management of patients failing on ART.

Introduction: The majority of studies from resource-limited settings only report short-term virological outcomes of patients on antiretroviral treatment (ART). We aim to describe the long-term durability of first-line ART and identify factors associated with long-term virological outcomes. Methods: At the Infectious Diseases Institute in Kampala, Uganda, 559 adult patients starting ART in 2004 were enrolled into a research cohort and monitored with viral load (VL) testing every six months for 10 years. We report the proportion and cumulative probability of 1) achieving virologic suppression (at least one VL 1000 copies/ml or one VL >5000, for those without a subsequent one); 3) treatment failure (not attaining virologic suppression or experiencing virologic failure). We used Cox regression methods to determine the characteristics associated with treatment failure. We included gender, baseline age, WHO stage, body mass index, CD4 count, propensity score for initial ART regimen, VL, time-dependent CD4 count and adherence. Results: Of the 559 patients enrolled, 472 (84.8%) had at least one VL (67 died, 13 were lost to follow-up, 4 transferred, 2 had no VL available); 73.6% started on d4T/3TC/nevirapine and 26.4% on AZT/3TC/efavirenz. Patients in the two groups had similar characteristics, except for the higher proportion of patients in WHO Stage 3/4 and higher VL in the efavirenz-based group. Four hundred thirty-nine (93%) patients achieved virologic suppression with a cumulative probability of 0.94 (confidence interval (CI): 0.92-0.96); 74/439 (16.9%) experienced virologic failure with a cumulative probability of 0.18 (CI: 0.15-0.22). In the multivariate analysis, initial d4T/3TC/nevirapine regimen (hazard ratio (HR): 3.02; CI: 3.02 (1.66-5.44, p < 0.001)) and baseline VL [greater than or equal to] 5 log10 copies/ml (HR: 2.29; CI: 1.29-4.04) were associated with treatment failures; patients of older age (HR: 0.87 per five-year increase; CI: 0.77-0.99), with adherence >95% (HR: 0.04; CI: 0.02-0.11) and with higher time-dependent CD4 count (HR: 0.94 per 50 cells/ml increase; CI: 0.92-0.99, p < 0.001) were less likely to experience treatment failure. Conclusions: The long-term virological outcomes from this cohort are promising and comparable to those from research-rich settings. Our results provide further evidence that efavirenz is associated with better virological outcomes. Keywords: antiretroviral treatment; treatments failure; long term outcomes., Introduction Access to life-saving antiretroviral treatment (ART) has rapidly expanded in resource-limited settings over the past decade [1]. The greatest increase in the number of HIV-positive patients receiving ART was [...]

Introduction: Cardiovascular disease (CVD) is the leading cause of death globally, representing 31% of all global deaths. HIV and long term anti-retroviral therapy (ART) are risk factors for development of CVD in populations of people living with HIV (PLHIV). CVD risk assessment tools are currently being applied to SSA populations, but there are questions about accuracy as well as implementation challenges of these tools in lower resource setting populations. We aimed to assess the level of agreement between the various cardiovascular screening tools (Data collection on Adverse effects of anti-HIV Drugs (D:A:D), Framingham risk score, WHO risk score and The Atherosclerotic Cardiovascular Disease Score) when applied to an HIV ART experienced population in Sub-Saharan Africa. Methods: This study was undertaken in an Anti-Retroviral Long Term (ALT) Cohort of 1000 PLHIV in care who have been on ART for at least 10 years in urban Uganda. A systematic review was undertaken to find the most frequently used screening tools from SSA PLHIV populations; these were applied to the ALT cohort. Levels of agreement between the resulting scores (those including lipids and non-lipids based, as well as HIV-specific and non-HIV specific) as applied to our cohort were compared. Prevalence Bias Adjusted Kappa was used to evaluate agreement between tools. Results: Overall, PLHIV in ALT cohort had a median score of 1.1–1.4% risk of a CVD event over 5 years and 1.7–2.5% risk of a CVD event over 10 years. There was no statistical difference in the risk scores obtained for this population when comparing the different tools, including comparisons of those with lipids and non-lipids, and HIV specific vs non-HIV specific. Conclusion: The various tools yielded similar results, but those not including lipids are more feasible to apply in our setting. Long-term cohorts of PLHIV in SSA should in future provide longitudinal data to evaluate existing CVD risk prediction tools for these populations. Inclusion of HIV and ART history factors to existing scoring systems may improve accuracy without adding the expense and technical difficulty of lipid testing. [ABSTRACT FROM AUTHOR]

Background: Despite increased antiretroviral therapy (ART) coverage and the raised CD4 threshold for starting ART, opportunistic infections (OIs) are still one of the leading causes of death in sub-Saharan Africa. There are few studies from resource-limited settings on long-term reporting of OIs other than tuberculosis. Methods: Patients starting ART between April 2004 and April 2005 were enrolled and followed-up for 10 years in Kampala, Uganda. We report incidences, patterns and risk factors using Cox proportional hazards models of OIs among all patients and among patients with CD4 cell counts >200 cells/μL. Results: Of the 559 patients starting ART, 164 patients developed a total of 241 OIs during 10 years of follow-up. The overall incidence was highest for oral candidiasis (25.4, 95% confidence interval (CI): 20.5–31.6 per 1000 person-years of follow-up), followed by tuberculosis (15.3, 95% CI: 11.7–20.1), herpes zoster (12.3, 95% CI: 9.1–16.6) and cryptococcal meningitis (3.0, 95% CI: 1.7–5.5). Incidence rates for all OIs were highest in the first year after ART initiation and decreased with the increase of the current CD4 cell count. Factors independently associated with development of OIs were baseline nevirapine-based regimens, time-varying higher viral load, time-varying lower CD4 cell count and time-varying lower hemoglobin. In patients developing OIs at a current CD4 cell count >200 cells/μL, factors independently associated with OI development were time-varying increase in viral load and time-varying decrease in hemoglobin, whereas a baseline CD4 cell count <50 cells/μL was protective. Conclusion: We report high early incidences of OIs, decreasing with increasing CD4 cell count and time spent on ART. Ongoing HIV replication and anemia were strong predictors for OI development independent of the CD4 cell count. Our findings support the recommendation for early initiation of ART and suggest close monitoring for OIs among patients recently started on ART, with low CD4 cell count, high viral load and anemia. [ABSTRACT FROM AUTHOR]

Purpose Little information is available on patients on antiretroviral treatment (ART) after a long-term period from sub-Saharan Africa, with the longest follow-up and related outcomes being after 10 years on ART. At the Infectious Diseases Institute (IDI) (Kampala, Uganda), we set up a cohort of patients already on ART for 10 years at the time of enrolment, who will be followed up for additional 10 years. Participants A prospective observational cohort of 1000 adult patients previously on ART for 10 years was enrolled between May 2014 and September 2015. Patients were eligible for enrolment if they were in their consecutive 10th year of ART regardless of the combination of drugs for both first- and second-line ART. Data were collected at enrolment and all annual study visits. Follow-up visits are scheduled once a year for 10 years. Biological samples (packed cells, plasma and serum) are stored at enrolment and follow-up visits. Findings to date Out of 1000 patients enrolled, 345 (34.5%) originate from a pre-existing research cohort at IDI, while 655 (65.5%) were enrolled from the routine clinic. Overall, 81% of the patients were on first line at the time of the enrolment in the ART long-term cohort, with the more frequent regimen being zidovudine plus lamivudine plus nevirapine (44% of the cohort), followed by zidovudine plus lamivudine plus efavirenz (22%) and tenofovir plus lamivudine or emtricitabine plus efavirenz (10%). At cohort enrolment, viral suppression was defined as HIV-RNA <400 copies/mL was 95.8%. Future plans Through collaboration with other institutions, we are planning several substudies, including the evaluation of the risk for cardiovascular diseases, the assessment of bone mineral density, screening for liver cirrhosis using fibroscan technology and investigation of drug-drug interactions between ART and common drugs used for non-communicable diseases. [ABSTRACT FROM AUTHOR]

Lifelong ART is essential to reducing HIV mortality and ending the epidemic, however the interplay between socioeconomic position and long-term outcomes of HIV-infected persons receiving antiretroviral therapy (ART) in sub-Saharan Africa is unknown. Furthering the understanding of factors related to long-term ART outcomes in this important region will aid the successful scale-up of ART programs. We enrolled 559 HIV-infected Ugandan adults starting ART in 2004–2005 at the Infectious Diseases Institute in Kampala, Uganda and followed them for 10 years. We documented baseline employment status, regular household income, education level, housing description, physical ability, and CD4 count. Viral load was measured every six months. Proportional hazard regression tested for associations between baseline characteristics and 1) mortality, 2) virologic failure, and 3) mortality or virologic failure as a composite outcome. Over ten years 23% (n = 127) of participants died, 6% (n = 31) were lost-to-follow-up and 23% (107/472) experienced virologic treatment failure. In Kaplan-Meier analysis we observed an association between employment and mortality, with the highest cumulative probability of death occurring in unemployed individuals. In univariate analysis unemployment and disease severity were associated with mortality, but in multivariable analysis the only association with mortality was disease severity. We observed an association between higher household income and an increased incidence of both virologic failure and the combined outcome, and an association between self-employment and lower incidence of virologic failure and the combined outcome when compared to unemployment. Formal education level and housing status were unrelated to outcomes. It is feasible to achieve good ten-year survival, retention-in-care, and viral suppression in a socioeconomically diverse population in a resource-limited setting. Unemployment appears to be related to adverse 10-year ART outcomes. A low level of formal education does not appear to be a barrier to successful long-term ART. [ABSTRACT FROM AUTHOR]

Since 2012, the WHO recommends lifelong ART with TDF+FTC/3TC+EFV for all HIV-positive pregnant and breastfeeding women (Option B-plus). In this analysis we describe the proportion of early and late transmission in mothers with high retention in Kampala, Uganda. We included 700 pregnant women from January 2012 to August 2014 with a follow-up extended to August 2016; the median age was 31 years (IQR: 26–35), 36.3% in WHO stage 3/4; median CD4 count was 447 cells/μL (IQR: 301–651) and 73.3% were already on ART for a median time of 28 (IQR: 10–57) months; 52% infants were male and median weight was 3.2 Kg (IQR: 2.5–3.5). Five hundred and sixty-five (80.7%) infants had at least one test for HIV; 22 (3.1%) infants died, all with unknown serostatus; 3 tested positive at week 6 and one additional at months 12 and 18. Two of the mothers of the 4 HIV-positive infants were ART-naïve at the time of pregnancy. We report very low documented HIV transmission comparable with those reported in clinical trials settings; however, demonstrating the efficacy of Option B-plus in terms of averted transmission in routine settings is challenging since high proportion of infants do not have documented HIV tests. [ABSTRACT FROM AUTHOR]

Introduction. We aim to describe the time of entry into care and factors associated with being lost to program (LTP) in pregnant women on Option B Plus in an integrated HIV and antenatal care (ANC) clinic in Uganda. Methods. We included all pregnant women enrolled into the integrated HIV-ANC clinic from January 2012 to 31st July 2014, while the follow up period extended up to October 30th 2015. LTP was defined as being out of care for ≥3 months. Results. Overall 856 women were included. Only 36.4% (86/236) of the women were enrolled in the first trimester. Overall 69 (8.1%) were LTP. In the multivariate analysis older women (HR: 0.80 per five-year increase, CI: 0.64–1.0, and P=0.060) and women on ART at the time of pregnancy (0.58, CI: 0.34–0.98, and P=0.040) were more likely not to be LTP. Among women already on ART at the time of pregnancy no factor was associated with LTP. Conclusion. Our results suggest the need for interventions to enhance prompt linkage of HIV positive women to HIV services for ART initiation and for increased retention particularly in young and ART naive women. [ABSTRACT FROM AUTHOR]

The objective of this paper was to investigate factors associated with time to first birth after first marriage among women in Uganda. The assessment was made using data sourced from the 2011 Uganda Demographic and Health survey. The analysis was done using a time-toevent approach involving life tables, log-rank and the Cox Proportional Hazards model. In the results, the median time to first birth after first marriage was 2 years (range, 1-36). The key predictors of having a live birth after first marriage were loss of a pregnancy either spontaneously or induced, knowledge of ovulation cycle and late sexual debut (p < 0.05). In particular, the chances of first birth after first marriage were lower among women who had ever lost a pregnancy and women having their sexual intercourse at a later age. On the contrary, the chances of having a first child after marriage were higher among women at higher ages at first marriage and those who were aware of their ovulation cycle. [ABSTRACT FROM AUTHOR]

Background: There is a high rate of lost to programme (LTP) in human immunodeficiency virus (HIV)-positive young adults transitioning from paediatric/adolescent to adult care. Methods: We describe and identify risk factors for LTP in all patients 18-23 y of age at the Infectious Diseases Institute (Kampala, Uganda) from 2010 to 2014. Results: A total of 260 of 907 young adults (28.6%) became LTP. Among those on antiretroviral treatment, 39.3% became LTP. We found that the only risk factor associated with LTP was being in World Health Organization stage 3 or 4. Conclusion: There is a need for tracing studies to evaluate the true vital status of LTP in this group. [ABSTRACT FROM AUTHOR]

Background: Short-medium term studies from sub-Saharan Africa show that, despite high early mortality, substantial loss to program, and high rates toxicity, patients on antiretroviral treatment have achieved outcomes comparable to those in developed settings. However, these studies were unable to account for long term outcomes of patients as they stayed longer on treatment. Objectives: We aim to describe ten years outcomes of one of the first cohort of HIV positive patients started on antiretroviral treatment (ART) in Sub-Saharan Africa. Methods: We report 10-years outcomes including mortality, retention, CD4-count response, virological outcomes, ART regimens change from a prospective cohort of 559 patients initiating ART and followed up for 10 years Uganda. Results: Of 559 patients, 69.1% were female, median age (IQR) was 38 (33–44) years, median CD4-count (IQR) 98 (21–163) cell/μL; 74% were started on stavudine, lamivudine and nevirapine, 26% on zidovudine, lamivudine and efavirenz. After 10 years 361 (65%) patients were still in the study; 127 (22.7%) had died; 30 (5%) were lost to follow-up; 27 (5%) transferred; 18 (3%) withdrew consent. The probability of death was high in the first year (0.15, 95%, CI 0.12–0.18). The median CD4 count increased from 98 to 589 cell/μL (IQR: 450–739 cell/μL) with a median increase of 357 cells/μL (IQR: 128–600 cells/μL); 7.4% never attained initial viral suppression and of those who did 31.7% experienced viral failure. Three hundred and two patients had at least one drug substitution while on first line after a median of 40 months; 66 (11.9%) of the patients were switched to a second line PI-based regimen due to confirmed treatment failure. Conclusions: Despite the high rate of early mortality due to advanced disease at presentation the outcomes from this cohort are encouraging, particularly the remarkable and incremental immune-recovery and a satisfactory rate of virologic suppression. [ABSTRACT FROM AUTHOR]

Epidemiological studies suggest a link between onchocerciasis and various forms of epilepsy, including nodding syndrome (NS). The aetiopathology of onchocerciasis associated epilepsy remains unknown. This case-control study investigated potential risk factors that may lead to NS and other forms of non-nodding epilepsy (OFE) in northern Uganda. We consecutively recruited 154 persons with NS (aged between 8 and 20 years), and age-frequency matched them with 154 with OFE and 154 healthy community controls. Participants' socio-demography, medical, family, and migration histories were recorded. We tested participants for O. volvulus serum antibodies. The 154 controls were used for both OFE and NS separately to determine associations. We recruited 462 people with a median age of 15 years (IQR 14, 17); 260 (56.4%) were males. Independent risk factors associated with the development of NS were the presence of O. volvulus antibodies [aOR 8.79, 95% CI (4.15–18.65), p-value < 0.001] and preterm birth [aOR 2.54, 95% CI (1.02–6.33), p-value = 0.046]. Risk factors for developing OFE were the presence of O. volvulus antibodies [aOR 8.83, 95% CI (4.48–17.86), p-value < 0.001] and being born in the period before migration to IDP camps [aOR 4.28, 95% CI (1.20–15.15), p-value = 0.024]. In conclusion, O. volvulus seropositivity was a risk factor to develop NS and OFE; premature birth was a potential co-factor. Living in IDP camps was not a risk factor for developing NS or OFE. [ABSTRACT FROM AUTHOR]