The 2000HIV study: Design, multi-omics methods and participant characteristics.

Background: Even during long-term combination antiretroviral therapy (cART), people living with HIV (PLHIV) have a dysregulated immune system, characterized by persistent immune activation, accelerated immune ageing and increased risk of non-AIDS comorbidities. A multi-omics approach is applied to a large cohort of PLHIV to understand pathways underlying these dysregulations in order to identify new biomarkers and novel genetically validated therapeutic drugs targets. Methods: The 2000HIV study is a prospective longitudinal cohort study of PLHIV on cART. In addition, untreated HIV spontaneous controllers were recruited. In-depth multi-omics characterization will be performed, including genomics, epigenomics, transcriptomics, proteomics, metabolomics and metagenomics, functional immunological assays and extensive immunophenotyping. Furthermore, the latent viral reservoir will be assessed through cell associated HIV-1 RNA and DNA, and full-length individual proviral sequencing on a subset. Clinical measurements include an ECG, carotid intima-media thickness and plaque measurement, hepatic steatosis and fibrosis measurement as well as psychological symptoms and recreational drug questionnaires. Additionally, considering the developing pandemic, COVID-19 history and vaccination was recorded. Participants return for a two-year follow-up visit. The 2000HIV study consists of a discovery and validation cohort collected at separate sites to immediately validate any finding in an independent cohort. Results: Overall, 1895 PLHIV from four sites were included for analysis, 1559 in the discovery and 336 in the validation cohort. The study population was representative of a Western European HIV population, including 288 (15.2%) cis-women, 463 (24.4%) non-whites, and 1360 (71.8%) MSM (Men who have Sex with Men). Extreme phenotypes included 114 spontaneous controllers, 81 rapid progressors and 162 immunological non-responders. According to the Framingham score 321 (16.9%) had a cardiovascular risk of >20% in the next 10 years. COVID-19 infection was documented in 234 (12.3%) participants and 474 (25.0%) individuals had received a COVID-19 vaccine. Conclusion: The 2000HIV study established a cohort of 1895 PLHIV that employs multi-omics to discover new biological pathways and biomarkers to unravel non-AIDS comorbidities, extreme phenotypes and the latent viral reservoir that impact the health of PLHIV. The ultimate goal is to contribute to a more personalized approach to the best standard of care and a potential cure for PLHIV.

Dolutegravir-based regimens in treatment-naive and treatment-experienced aging populations: analyses of 6 phase III clinical trials.

Background: Older adults living with HIV (OALWH) are a growing population facing unique challenges to successful antiretroviral therapy.Objective: To assess efficacy and safety profiles of antiretroviral regimens, including those containing dolutegravir, in OALWH.Methods: Combined data from 6 phase III/IIIb trials in treatment-naive (ARIA, FLAMINGO, SINGLE, SPRING-2; N = 2634) and treatment-experienced (DAWNING, SAILING; N = 1339) participants receiving dolutegravir- or non-dolutegravir-based regimens were analyzed by age (<50, ≥50 to <65, and ≥65 years). Baseline data included comorbidities and numbers of concomitant medications. Week 48 efficacy outcomes included virologic response (HIV-1 RNA <50 copies/mL) and CD4+ cell count change from baseline. Safety outcomes included incidence of adverse events (AEs), serious AEs, and AE-related withdrawals.Results: Use of ≥5 concomitant medications was more frequently reported among treatment-naive and treatment-experienced participants aged ≥50 to <65 (30% [90/296] and 25% [57/227], respectively) and ≥65 years (43% [10/23] and 29% [4/14]) than among those aged <50 years (13% [310/2315] and 11% [118/1098]). Comorbidities were more prevalent in the older age groups. For dolutegravir-based regimens, Week 48 rates of virologic response and change in CD4+ cell count were similar across age groups (treatment naive, 80-87% and 234-251 cells/mm3; treatment experienced, 70-100% and 105-156 cells/mm3, respectively). There were no major differences in safety outcomes in each age group.Conclusions: In these analyses of combined phase III/IIIb trial data, efficacy and safety of dolutegravir-based regimens were generally similar across age groups in treatment-naive or treatment-experienced participants. Polypharmacy and comorbidities were more common among OALWH than those aged <50 years.

Reduction and enhancement of Plasmodium falciparum transmission by endemic human sera.

Transmission of Plasmodium falciparum from man to mosquito can be affected by human sera. Whereas serum-dependent reduction of transmission has been shown to be reproducible, there is limited evidence for enhancement of transmission. We aimed to assess the prevalence and reproducibility of transmission enhancement (TE) by human sera from different geographic areas (n = 642), in comparison with the capacity for transmission reduction (TR). The overall prevalence of TE (7%) was lower than that of TR (48%) and its effect generally weaker but reproducible in repeated measurements. TR but not TE showed a significant association with the presence of serum antibodies against Pfs48/45 and a non-significant trend to the presence of anti-Pfs230 antibodies.

Rapid onset of transmission-reducing antibodies in javanese migrants exposed to malaria in papua, indonesia.

Transmission of Plasmodium falciparum malaria is initiated by sexual stages in the mosquito. Anti-Pfs48/45 and anti-Pfs230 sexual stage antibodies that are ingested together with parasites can reduce parasite development and subsequently malaria transmission. Acquisition of sexual stage immunity was studied in a cohort of 102 non-immune Javanese individuals migrating to hyperendemic Papua Indonesia. Seroprevalence of antibodies against Pfs48/45 and Pfs230 and functional transmission-reducing activity (TRA) were measured upon arrival and at 6, 12, and 24 months. Asexual parasitemia and gametocytemia were assessed every two weeks. The TRA and seroreactivity increased with the number of P. falciparum infections. The longitudinally sustained association between TRA and antibodies against Pfs48/45 (odds ratio [OR] = 3.74, 95% confidence interval [CI] = 1.51-9.29) and Pfs230 (OR = 3.72, 95% CI = 1.36-10.17) suggests that functional transmission reducing immunity is acquired after limited exposure to infection.

Transmission of Plasmodium falciparum in urban Yaoundé, Cameroon, is seasonal and age-dependent.

Data on malaria transmission intensity and prevalences of asexual parasites and of gametocytes were obtained in an urban district of Yaoundé, Cameroon. The transmission level from mosquito to human was determined by indoor night capture of mosquitoes on human volunteers, revealing a calculated entomological inoculation rate of 34 infectious bites per person per year. Only Anopheles gambiae and A. funestus contributed to malaria transmission and their distribution was seasonal. Cross-sectional surveys every 2 months from July 1999 to May 2000 (n = 965) showed average annual prevalences of 35% Plasmodium falciparum asexual parasites (range 29-38%) and 4.4% gametocytes (range 0-6.7%). Prevalence of high parasitaemia (> 400 parasites/microL) and of gametocytes was seasonal. Prevalence of asexual parasitaemias and of gametocytaemias was age-dependent. The potential infectious reservoir in this area is dominated by the age group 0-15 years, representing 75% of carriers of asexual parasites (P < 0.001), 85% of carriers of high parasitaemias (P < 0.001), and 83% of gametocyte carriers (P = 0.03). Full year logistic models developed from the available data accurately predicted parasite prevalences in subsequent analyses, thus permitting a precise determination of study samples for intervention and seroepidemiology studies, and analysis of the infectious reservoir in this area.

Distribution of HPV genotypes in cervical intraepithelial lesions and cervical cancer in Tanzanian women.

BACKGROUND: Infection with human papillomavirus (HPV) is associated with uterine cervical intraepithelial neoplasia (CIN) and invasive cancers (ICC). Approximately 80% of ICC cases are diagnosed in under-developed countries. Vaccine development relies on knowledge of HPV genotypes characteristic of LSIL, HSIL and cancer; however, these genotypes remain poorly characterized in many African countries. To contribute to the characterization of HPV genotypes in Northeastern Tanzania, we recruited 215 women from the Reproductive Health Clinic at Kilimanjaro Christian Medical Centre. Cervical scrapes and biopsies were obtained for cytology and HPV DNA detection. RESULTS: 79 out of 215 (36.7%) enrolled participants tested positive for HPV DNA, with a large proportion being multiple infections (74%). The prevalence of HPV infection increased with lesion grade (14% in controls, 67% in CIN1 cases and 88% in CIN2-3). Among ICC cases, 89% had detectable HPV. Overall, 31 HPV genotypes were detected; the three most common HPV genotypes among ICC were HPV16, 35 and 45. In addition to these genotypes, co-infection with HPV18, 31, 33, 52, 58, 68 and 82 was found in 91% of ICC. Among women with CIN2-3, HPV53, 58 and 84/83 were the most common. HPV35, 45, 53/58/59 were the most common among CIN1 cases. CONCLUSIONS: In women with no evidence of cytological abnormalities, the most prevalent genotypes were HPV58 with HPV16, 35, 52, 66 and 73 occurring equally. Although numerical constraints limit inference, findings that 91% of ICC harbor only a small number of HPV genotypes suggests that prevention efforts including vaccine development or adjuvant screening should focus on these genotypes.

The effect of raltegravir on the glucuronidation of lamotrigine.

The authors studied the effect of raltegravir on the pharmacokinetics of the antiepileptic agent lamotrigine. Twelve healthy volunteers (group A) received 400 mg raltegravir twice daily from days 1 to 5. On day 4, a single dose of 100 mg lamotrigine was administered. After a washout period, participants received a second single dose of 100 mg of lamotrigine but now without raltegravir (day 32). In group B, 12 participants received the same treatment as in group A but in reverse order. On days 4 and 32, 48-hour pharmacokinetic curves were drawn. Geometric mean ratios (+90% confidence intervals [CIs]) of lamotrigine area under the plasma concentration-time curve (AUC(0-->48)) and peak plasma concentration (C(max)) for raltegravir + lamotrigine versus lamotrigine alone were 0.99 (0.96-1.01) and 0.94 (0.89-0.99), respectively. The mean ratio of the AUC(0-->48) of lamotrigine-2N-glucuronide to lamotrigine was similar when lamotrigine was taken alone (0.35) or when taken with raltegravir (0.36). Raltegravir does not influence the glucuronidation of lamotrigine.