2 Minute Medicine Rewind May 6, 2019

Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study

Early evidence has suggested a strong association between HIV viral load and the risk of transmission to an HIV-negative partner, as well as a significant reduction in transmission rates with early initiation of antiretroviral therapy and viral suppression among HIV-positive partners. Previous studies have largely examined HIV transmission rates with sexual intercourse in the setting of virally-suppressive therapy in heterosexual couples with variable degrees of condom use. However, evidence around HIV transmission risk through condomless sex in serodifferent gay couples involving an HIV-positive partner on antiretroviral therapy is limited. The previously conducted PARTNER1 study showed no linked transmissions in 888 serodifferent heterosexual and gay couples who endorsed condomless sex while on virally suppressive antiretroviral therapy, but did not provide sufficient follow-up to exclude a significant upper limit of risk for zero transmissions in gay men. In this prospective multicenter observational extension study (PARTNER2) across 14 countries, 972 serodifferent gay couples who reported engaging in condomless sex were recruited between September 2010 and July 2017 and followed up for a median of 2.0 years (IQR 1.1 to 3.5 years) to evaluate incidence rates of HIV transmission. At study visits, participants completed sexual behavior questionnaires, HIV testing for the HIV-negative partner, and viral load testing for the HIV-positive partner. While condomless anal sex was reported a total of 76,088 times in 1593 eligible couple-years, no linked within-couple HIV transmissions were reported (HIV transmission rate of 0%; upper 95% CI 0.23 per 100 couple-years). Of note, 288 (37%) of 777 HIV-negative men in the study reported condomless sex with other partners, and 15 new HIV infections were noted during follow-up, of which all were deemed to be phylogenetically unrelated to the HIV positive partner’s viral haplotype. This study therefore provides conclusive evidence that the risk of HIV transmission in gay couples through condomless anal sex is effectively 0% with viral load suppression. This is in line with previous evidence in heterosexual couples, supporting an “undetectable equals untransmissible” message, and encouraging early testing and initiation of early treatment.

Gentamicin compared with ceftriaxone for the treatment of gonorrhoea (G-ToG): a randomised non-inferiority trial

Gonorrhea is a common sexually transmitted infection associated with local inflammation causing genital pain, pelvic inflammatory disease, increased HIV acquisition risk, and other related complications. While ceftriaxone is the current first-line therapy, there is growing concern around emerging antimicrobial resistance, with limited evidence supporting other treatments. Gentamicin has been associated with cure rates ranging from 62% to 100%. However, studies reporting these rates have been poorly described with respect to their methodologies and therefore incur a high risk of bias. There have also been concerns surrounding gentamicin and gastrointestinal, ototoxic and nephrotoxic adverse effects. In this randomized non-inferiority trial, 720 adults were randomly assigned to receive a single intramuscular dose of either gentamicin 240 mg (n = 358) or ceftriaxone 500 mg (n = 362), in addition to a single 1 g dose of azithromycin, to assess the effectiveness of gentamicin as an alternative to ceftriaxone for treatment of gonorrhoea. A non-inferiority risk difference margin with a lower confidence limit of 5% was established. Researchers found that 299 (98%) participants in the ceftriaxone group compared to 267 (91%) in the gentamicin group achieved the primary outcome of clearance of N. gonorrhoeae infection after two weeks of treatment across all sites (genital, pharyngeal and rectal) (adjusted risk difference -6.4%, 95% CI -10.4% to -2.4%). Greater proportions of participants receiving ceftriaxone had clearance of pharyngeal infections (96% vs. 80%; adjusted risk difference -15.3%, 95% CI -24.0% to -6.5%) and rectal infections (98% vs. 90%; adjusted risk difference -7.8%, 95% CI -13.6% to -2.0%). Gentamicin performed better than ceftriaxone for genital gonorrhea, with clearance achieved in 98% vs. 94% of participants, respectively (adjusted risk difference -4.4%, 95% CI -8.7% to 0%). Side-effect profiles were similar between groups. This study therefore shows that while gentamicin plus azithromycin cannot be considered non-inferior to current standard therapy with ceftriaxone and azithromycin and is not suggested as a first-line regimen, its use may be appropriate for isolated genital infection, or for patients with ceftriaxone-related allergy, intolerance or resistance.

Opioid agonist treatment dosage and patient-perceived dosage adequacy, and risk of hepatitis C infection among people who inject drugs

The opioid epidemic has been associated with rising hepatitis C virus (HCV) infection incidence in North America among those who inject drugs. While opioid agonist therapy may reduce HCV infection risk, the role of dosage of such therapy on this association is unclear. Given an increasing focus on global eradication of HCV infections and use of opioid agonist therapy, this prospective observational study aimed to examine the association between the prescribed dose of opioid agonist therapy and patient-perceived dosage adequacy with the risk of HCV infection among 513 adult intravenous drug users in Montreal, Canada. Participants were tested for HCV antibodies or RNA and were administered a behavioural questionnaire regarding opioid agonist therapy exposure, prescribed dosage and perceived dosage adequacy, on a 6-month basis initially, followed by a 3-month basis. Researchers found an incidence of 11.8 acquired hepatitis C infections over 100 person-years, with 168 out of 513 participants infected. The relative risk of HCV infection acquisition varied across opioid agonist treatment dosages, with those receiving high dosages (adjusted HR 0.43, 95% CI 0.23 to 0.84) and dosages perceived to be adequate (adjusted HR 0.61, 95% CI 0.25 to 1.50) having the lowest risk. Those receiving low doses perceived to be inadequate having the highest risk (adjusted HR 1.94, 95% CI 1.11 to 3.39) compared to intravenous drug users not on opioid agonist therapy. The results of this study therefore suggest that the risk of HCV infection varies considerably with dosage of opioid agonist treatment and patient-perceived adequacy of dose.

Preterm birth and risk of chronic kidney disease from childhood into mid-adulthood: national cohort study

Fetal nephrogenesis is most significant in the third trimester of pregnancy, and is interrupted by preterm birth before 37 weeks of gestation, resulting in lower nephron numbers and the development of hypertension and progressive renal disease later in life. While low birth weight has been associated with chronic kidney disease and preterm birth has been associated with neonatal acute renal injury, the long-term risk of chronic kidney disease with preterm birth has not been directly examined. In this Swedish registry-based national cohort study of 4,195,2294 singleton live births between 1973 and 2014, subjects were followed up to investigate the relation between preterm birth (gestational age <37 weeks) and risk of CKD from childhood into mid-adulthood. Cases were identified using ICD codes from registered primary and secondary diagnoses in hospital and outpatient registries (maximum age 43 years). Of 4,305 (0.1%) participants who were given a diagnosis of chronic kidney disease, pre-term (<37 weeks) and extremely pre-term birth (<28 weeks) were associated with approximately two-fold and three-fold increased risk, respectively (adjusted HR 1.94, 95% CI 1.74 to 2.16, p<0.001; HR 3.01, 95% CI 1.67 to 5.45, p<0.001). The association was strongest between ages 0 to 9 years (adjusted HR 5.09, 95% CI 4.11 to 6.31, p<0.001), but was significant across all studied age groups up to 43 years of age affecting both males and females. The findings of this study therefore support the hypothesis that pre-term and early-term births are strong risk factors for chronic kidney disease, particularly between childhood and mid-adulthood, warranting close long-term follow-up and renal function monitoring, counselling, and risk factor modification where possible.

Association of socioeconomic status and brain injury with neurodevelopmental outcomes of very preterm children

Preterm birth remains a leading cause of lifelong neurodevelopmental disability. While the effect of brain injury on neurodevelopmental disability has been studied extensively, far less is known with respect to the role of environments and experiences in moderating these associations. In this prospective cohort study, preterm neonates (24-32 weeks’ gestation) born between August 16, 2006 and September 9, 2013 at British Columbia Women’s Hospital in Vancouver, Canada, were followed up and studied to determine the association of brain injury and maternal education with motor and cognitive outcomes at age 4.5 years in very preterm neonates. At 4.5 years of age, a full-scale intelligence quotient (FSIQ) was assessed using the Wechsler Primary and Preschool Scale of Intelligence (fourth edition). Motor outcomes were assessed using the Movement Assessment Battery for Children, second edition (MABC2). Of the 226 survivors comprising the study, neurodevelopmental outcome was assessed in 170 patients. Maternal level of education was available for 197 patients. Researchers found that mean (SD) FSIQ at 4.5 years was 102.0 (14.6). The mean (SD) FSIQ score in children whose mothers had a postgraduate degree (108.30 (9.45)) was significantly higher than the mean (SD) FSIQ scores of both the undergraduate degree group (98.66 (19.65), p=0.01) and the primary or secondary school group (96.24 (19.96), p=0.02). The mean FSIQ scores of the undergraduate and primary or secondary school groups did not differ. With respect to motor outcomes, researchers found that the median M-ABC2 percentile score at age 4.5 years was 37 (IQR 5-63). The median M-ABC2 percentile score was significantly higher in children whose mothers had a postgraduate degree (56.5 (16-91])) than in those in the undergraduate degree group (25 (2-63)) (p =0 .03). When comparing cognitive scores in children with and without brain injury, researchers found that in the absence of brain injury, the higher socioeconomic status (SES) group achieved a predicted FSIQ 7.4 points higher (95% CI 6.99 to 8.83, p<0.001) than the lower SES group. In the presence of brain injury, the association with SES increased, with the higher SES group having a mean increase of 13.7 points (95% CI 13.34 to 14.25, p<0.001) relative to the lower SES group. Based on the best model to assess FSIQ while accounting for gestational age, standardized β coefficients demonstrated the effect size of maternal education (standardized β = 0.21) was similar to that of white matter injury volume (standardized β = 0.23) and intraventricular hemorrhage (standardized β = 0.23). The best-performing model to assess for motor outcome accounting for gestational age included being small for gestational age, severe intraventricular hemorrhage, white matter injury volume, and chronic lung disease. This study therefore shows that at preschool age, the cognitive outcome of preterm neonates was associated with maternal education and neonatal brain injury. The association of brain injury with poorer cognition was attenuated in children born to mothers of higher education level.

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