Clinical outcomes after first-line HIV treatment failure in South Africa: the next cascade of care.

INTRODUCTION: There is limited literature on the appropriateness of viral load (VL) monitoring and management of detectable VL in public health settings in rural South Africa. METHODS: We analysed data captured in the electronic patient register from HIV-positive patients ≥ 15 years old initiating antiretroviral therapy (ART) in 17 public sector clinics in rural KwaZulu-Natal, during 2010-2016. We estimated the completion rate for VL monitoring at 6, 12, and 24 months. We described the cascade of care for those with any VL measurement ≥ 1000 HIV-1 RNA copies/mL after ≥ 20 weeks on ART, including the following proportions: (1) repeat VL within 6 months; (2) re-suppressed; (3) switched to second-line regimen. RESULTS: There were 29 384 individuals who initiated ART during the period [69% female, median age 31 years (interquartile range 25-39)]. Of those in care at 6, 12, and 24 months, 40.7% (9861/24 199), 34% (7765/22 807), and 25.5% (4334/16 965) had a VL test at each recommended time-point, respectively. The VL results were documented at all recommended time-points for 12% (2730/22 807) and 6.2% (1054/16 965) of ART-treated patients for 12 and 24 months, respectively. Only 391 (18.3%) of 2135 individuals with VL ≥ 1000 copies/mL on first-line ART had a repeat VL documenting re-suppression or were appropriately changed to second-line with persistent failure. Completion of the treatment failure cascade occurred a median of 338 days after failure was detected. CONCLUSION: We found suboptimal VL monitoring and poor responses to virologic failure in public-sector ART clinics in rural South Arica. Implications include increased likelihood of morbidity and transmission of drug-resistant HIV.

Findings from home-based HIV testing and facilitated linkage after scale-up of test and treat in rural South Africa: young people still missing.

OBJECTIVES: The aim of the study was to estimate rates of linkage to HIV care and antiretroviral treatment (ART) initiation after the introduction of home-based HIV counselling and testing (HBHCT) and telephone-facilitated support for linkage in rural South Africa. METHODS: A population-based prospective cohort study was carried out in KwaZulu Natal, South Africa. All residents aged ≥ 15 years were eligible for HBHCT. Those who tested positive and were not in care were referred for ART at one of 11 public-sector clinics. Individuals who did not attend the clinic within 2 weeks were sent a short message service (SMS) reminder; those who had not attended after a further 2 weeks were telephoned by a nurse counsellor, to discuss concerns and encourage linkage. Kaplan-Meier methods were used to estimate the proportion of newly diagnosed individuals linking to care and initiating ART. RESULTS: Among 38 827 individuals visited, 26% accepted HBHCT. Uptake was higher in women than in men (30% versus 20%, respectively), but similar in people aged < 30 years and ≥ 30 years (28% versus 26%, respectively). A total of 784 (8%) tested HIV positive, of whom 427 (54%) were newly diagnosed. Within 6 months, 31% of women and 18% of men < 30 years old had linked to care, and 29% and 16%, respectively, had started ART. Among those ≥ 30 years, 41% of women and 38% of men had linked to care within 6 months, and 41% and 35%, respectively, had started ART. CONCLUSIONS: Despite facilitated linkage, rates of timely linkage to care and ART initiation after HBHCT were very low, particularly among young men. Innovations are needed to provide effective HIV care and prevention interventions to young people, and thus maximize the benefits of universal test and treat.

Effect of cotrimoxazole prophylaxis on malaria occurrence in HIV-infected patients on antiretroviral therapy in sub-Saharan Africa.

OBJECTIVE: To systematically review the evidence on the effect of cotrimoxazole (CTX) on malaria in HIV-positive individuals on antiretroviral therapy (ART). METHODS: Web of Science, PubMed and MEDLINE, EMBASE, Global Health and Cochrane Library databases were searched using terms for malaria, HIV and CTX. Studies meeting the inclusion criteria were reviewed and assessed for bias and confounding. RESULTS: Six studies (in Uganda, Kenya, Malawi, Zambia and Zimbabwe) had relevant data on the effect of CTX on malaria in patients on ART: four were observational cohort studies (OCS) and two were randomised controlled trials (RCTs); two were in children and one in women only. Samples sizes ranged from 265 to 2200 patients. Four studies compared patients on ART and CTX with patients on ART alone; 2 (RCTs) found a significant increase in smear-positive malaria on ART alone: (IRR 32.5 CI = 8.6-275.0 and HR 2.2 CI = 1.5-3.3) and 2 (OCS) reported fewer parasitaemia episodes on CTX and ART (OR 0.85 CI = 0.65-1.11 and 3.6% vs. 2.4% of samples P = 0.14). One OCS found a 76% (95% CI = 63-84%) vs. 83% (95% CI = 74-89%) reduction in malaria incidence in children on CTX and ART vs. on CTX only, when both were compared with HIV-negative children. The other reported a 64% reduction in malaria incidence after adding ART to CTX (RR = 0.36, 95% CI = 0.18-0.74). The 2 RCTs were unblinded. Only one study reported adherence to CTX and ART, and only two controlled for baseline CD4 count. CONCLUSION: Few studies have investigated the effect of CTX on malaria in patients on ART. Their findings suggest that CTX is protective against malaria even among patients on ART.

The impact of the COVID-19 pandemic on the provision & utilisation of primary health care services in Goma, Democratic Republic of the Congo, Kambia district, Sierra Leone & Masaka district, Uganda.

INTRODUCTION: This study aimed to determine whether the COVID-19 pandemic had an impact on essential primary healthcare services at public primary healthcare facilities. METHODS: The number of weekly consultations for antenatal care (ANC), outpatient (OPD), immunisations (EPI), family planning (FP) and HIV services, between January 2018 and December 2020, were collected from 25 facilities in Masaka district, Uganda, 21 in Goma, and 29 in Kambia district, Sierra Leone. Negative binomial regression models accounting for clustering and season were used to analyse changes in activity levels between 2018, 2019 and 2020. RESULTS: In Goma, we found no change in OPD, EPI or ANC consultations, FP was 17% lower in March-July 2020 compared to 2019, but this recovered by December 2020. New diagnoses of HIV were 34% lower throughout 2020 compared to 2019. In Sierra Leone, compared to the same periods in 2019, facilities had 18-29% fewer OPD consultations throughout 2020, and 27% fewer DTP3 doses in March-July 2020. There was no evidence of differences in other services. In Uganda there were 20-35% fewer under-5 OPD consultations, 21-66% fewer MCV1 doses, and 48-51% fewer new diagnoses of HIV throughout 2020, compared to 2019. There was no difference in the number of HPV doses delivered. CONCLUSIONS: The level of disruption varied across the different settings and qualitatively appeared to correlate with the strength of lockdown measures and reported attitudes towards the risk posed by COVID-19. Mitigation strategies such as health communications campaigns and outreach services may be important to limit the impact of lockdowns on primary healthcare services.

Does the number of doses matter? A qualitative study of HPV vaccination acceptability nested in a dose reduction trial in Tanzania.

BACKGROUND: The multi-dose regimen is a known barrier to successful human papillomavirus (HPV) vaccination. Emerging evidence suggests that one vaccine dose could protect against HPV. While there are clear advantages to a single dose schedule, beliefs about vaccine dosage in low and middle income countries (LMICs) are poorly understood. We investigated acceptability of dose-reduction among girls, and parents/guardians of girls, randomised to receive one, two or three doses in an HPV vaccine dose-reduction and immunobridging study (DoRIS trial) in Tanzania. METHODS: Semi-structured interviews with girls (n = 19), and parents/guardians of girls (n = 18), enrolled in the study and completing their vaccine course. RESULTS: Most participants said they entrusted decisions about the number of HPV vaccine doses to experts. Random allocation to the different dose groups did not feature highly in the decision to participate in the trial. Given a hypothetical choice, girls generally said they would prefer fewer doses in order to avoid the pain of injections. Parental views were mixed, with most wanting whichever dose was most efficacious. Nonetheless, a few parents equated a higher number of doses with greater protection. CONCLUSION: Vaccine trials and programmes will need to employ careful messaging to explain that one dose offers sufficient protection against HPV should emerging evidence from ongoing dose-reduction clinical trials support this.

Bacterial vaginosis in female facility workers in north-western Tanzania: prevalence and risk factors.

OBJECTIVES: To determine prevalence of, and risk factors for, bacterial vaginosis (BV) among herpes simplex virus (HSV) 2 seropositive Tanzanian women at enrollment into a randomised, placebo-controlled trial of HSV suppressive treatment. METHODS: 1305 HSV-2 seropositive women aged 16-35 years working in bars, guesthouses and similar facilities were interviewed, examined and tested for HIV, syphilis, Neisseria gonorrhoeae, Chlamydia trachomatis, BV, candidiasis and trichomoniasis. Factors associated with BV were analysed using logistic regression to estimate odds ratios and 95% confidence intervals. RESULTS: BV prevalence was 62.9%; prevalence of Nugent score 9-10 was 16.1%. Independent risk factors for BV were work facility type, fewer dependents, increasing alcohol consumption, sex in the last week (adjusted OR 2.03; 95% CI 1.57 to 2.62), using cloths or cotton wool for menstrual hygiene, HIV (adjusted OR 1.41; 95% CI 1.09 to 1.83) and Trichomonas vaginalis infection. There was no association between BV and the frequency or method of vaginal cleansing. However, BV was less prevalent among women who reported inserting substances to dry the vagina for sex (adjusted OR 0.44; 95% CI 0.25 to 0.75). CONCLUSION: BV was extremely prevalent among our study population of HSV-2 positive female facility workers in North-western Tanzania. Although recent sex was associated with increased BV prevalence, vaginal drying was associated with lower BV prevalence. Further studies of the effects of specific practices on vaginal flora are warranted.

Combined analysis of three crossover clinical pharmacology studies of effects of rabeprazole and esomeprazole on 24-h intragastric pH in healthy volunteers.

AIM: To compare antisecretory effects of rabeprazole and esomeprazole after single and repeat dosing in Helicobacter pylori-negative healthy volunteers. METHODS: Results were pooled from three smaller, open, crossover, randomized studies to obtain data from 80 subjects. The studies compared: (a) 5 days' dosing of 20 mg rabeprazole and esomeprazole (n = 24); (b) single doses of rabeprazole 20 mg and esomeprazole 40 mg (n = 27) and (c) 5 days' dosing of rabeprazole 10 mg and esomeprazole 20 mg (n = 29). Washout periods were > or =14 days. Intragastric pH was recorded continuously for 24 h on days 0, 1 and 5. RESULTS: Single doses of rabeprazole 20 mg maintained 24-h intragastric pH >4 for longer than esomeprazole 20 mg (45% vs. 32%; P < 0.001); rabeprazole 20 mg and esomeprazole 40 mg were equivalent in their effects. After 5 days' dosing, rabeprazole 20 mg maintained pH >4 for longer than esomeprazole 20 mg (62% vs. 56%; P = 0.046); the reverse was true for esomeprazole 20 mg vs. rabeprazole 10 mg (56% vs. 48%; P = 0.035). In general, intragastric pH AUC during 0-5 h after dosing was higher after esomeprazole than rabeprazole, whereas the reverse was true during the night. CONCLUSIONS: The order of effects on 24-h pH was: rabeprazole 10 mg < or = esomeprazole 20 mg < rabeprazole 20 mg = esomeprazole 40 mg. Esomeprazole acts faster, whereas rabeprazole's effect lasts longer.

Pharmacodynamic effects of single doses of rabeprazole 20 mg and pantoprazole 40 mg in patients with GERD and nocturnal heartburn.

BACKGROUND: Rabeprazole and pantoprazole are both used for symptomatic treatment of gastro-oesophageal reflux disease (GERD). Speed and duration of acid suppression and intensity of effect after a single dose may be important pharmacodynamic properties in clinical use. AIM: To compare antisecretory effects of single doses of rabeprazole and pantoprazole in patients with GERD and a history of nocturnal heartburn. METHODS: An open-label, randomized, two-way crossover, clinical pharmacology study was conducted. Twenty-nine Helicobacter pylori-negative GERD patients (17 men, mean age 44 years), with a history of nocturnal heartburn (mean frequency 4.7 episodes/week), received a single dose of rabeprazole 20 mg or pantoprazole 40 mg, with a 14-day 'washout'. Intragastric pH was recorded continuously from 24 h before to 24 h after dosing. RESULTS: Mean area under the intragastric pH-time curve (AUC) was significantly higher after dosing with rabeprazole 20 mg than with pantoprazole 40 mg in all time intervals analysed, including night (P 3 and >4 was significantly greater after rabeprazole than pantoprazole in all time intervals (P

Pharmacokinetics, safety and tolerability of three dosage regimens of buccal adhesive testosterone tablets in healthy men suppressed with leuprorelin.

We used a randomised, double-blind, crossover design to evaluate the pharmacokinetics, safety and tolerability of three doses of buccal adhesive testosterone tablets (BATT). Twenty-four healthy men, whose endogenous testosterone was suppressed to

Effects of rabeprazole, 20 mg, or esomeprazole, 20 mg, on 24-h intragastric pH and serum gastrin in healthy subjects.

AIM: To compare the antisecretory effects of rabeprazole and esomeprazole in an open, randomized, two-way crossover, clinical pharmacology study. METHODS: Twenty-four healthy subjects (14 men, 10 women; mean age 26.8 years) received rabeprazole 20 mg or esomeprazole 20 mg daily on days 1-5, with a 14-day 'wash-out'. Intragastric pH was recorded continuously, and serum gastrin measured, on days 0, 1 and 5. RESULTS: On day 0, mean intragastric pH AUC was significantly higher before the esomeprazole than before the rabeprazole treatment in four of the five time intervals analysed. On days 1 and 5, mean intragastric pH AUC was higher after rabeprazole than esomeprazole during 5-11, 14-24 and 0-24 h after dosing. Mean pH AUC in the first 5 h after dosing on day 5 was higher after esomeprazole than rabeprazole (P=0.012). On day 1, mean per cent times pH > 3 and > 4 were significantly greater after rabeprazole than esomeprazole during 0-14, 14-24 and 0-24 h. On day 5, mean serum gastrin AUC0-4 was higher (P = 0.017) after rabeprazole than esomeprazole (335 vs. 316 pg/mL.h). CONCLUSION: In this clinical pharmacology study, rabeprazole 20 mg daily was more effective than esomeprazole 20 mg daily in increasing intragastric pH and maintaining pH > 3 and > 4. On day 5, mean pH AUC was higher after esomeprazole than rabeprazole.

A mosquito densovirus infecting Aedes aegypti and Aedes albopictus from Thailand.

A previously undescribed mosquito densovirus was detected in colonies of Aedes aegypti and Ae. albopictus from Thailand, using a polymerase chain reaction (PCR)-based assay. Phylogenetic analysis of this virus showed it to be most closely related to ADNV isolated from Russian Ae. aegypti. Both Aedes species were susceptible to oral infection with the Thai-strain virus. Larval mortality for Ae. albopictus was higher (82%) than for Ae. aegypti (51%). Aedes aegypti were able to transmit the virus vertically to a high (58%) proportion of G1 progeny, and the virus was maintained persistently for up to six generations. A PCR survey of adult Ae. aegypti and Ae. albopictus in Thailand indicated that only Ae. aegypti are infected in the field, with an overall prevalence of 44%. Densovirus infection in adult Ae. aegypti showed distinct seasonal variation. The Thai strain densovirus may play a role in structuring Ae. albopictus and Ae. aegypti populations in nature.

Epidemiology of endemic Oropouche virus transmission in upper Amazonian Peru.

A cross-sectional serosurvey of a rural community near Iquitos, Peru was conducted to determine Oropouche (ORO) virus antibody prevalence and risk factors for human infection. Venous blood samples, and demographic, social, and risk factor data were obtained from people age five years of age and older who lived in the village of Santa Clara on the Nanay River, a tributary of the Amazon River. Sera were tested for ORO viral antibody by an ELISA. The specificity of viral antibody reactivity was determined by a standard plaque-reduction neutralization test. Interview data were analyzed by univariate and multiple logistic regression to determine which variables were statistically associated with previous ORO viral infection, as indicated by the presence of IgG antibody. Final models were evaluated based on log-likelihood and Wald chi-square. Clustering of seropositive residents within houses was analyzed by the method of Walter. Among 1,227 persons sampled, 33.7% (n=414) were positive for ORO viral IgG antibody. Overall, antibody prevalence was similar for males (33.9%) and females (33.6%), and increased significantly with age for both sexes to include more than half of persons more than 25 years of age. The length of residence in the village was positively associated with serologic status; persons who had moved to the village within the past 15 years were less likely to be seropositive than life-long residents of the same age. Antibody prevalence among immigrants who had lived in Santa Clara more than 15 years was similar to that in life-long residents. The activity most predictive of previous ORO viral infection was travel to forest communities and travel to Iquitos. No evidence of spatial heterogeneity in ORO virus antibody distribution was observed. Results suggested that endemic transmission of ORO virus in this region has been ongoing during many decades, and that people are at considerable risk of infection.

Wolbachia infection and expression of cytoplasmic incompatibility in Armigeres subalbatus (Diptera: Culicidae).

Polymerase chain reaction screening revealed that Armigeres subalbatus (Coquillett), a vector of filariasis, was infected with the intracellular bacteria Wolbachia. Laboratory crosses between infected males and uninfected females resulted in less than half the number of offspring than control crosses between uninfected individuals when young (2- to 3-d-old) males were used in the cross. However, imcompatibility was lost when old (14- to 17-d-old) males were used. Field-collected females did not show detectable cytoplasmic incompatibility, and this may be because of the age at which males mate in the field. We used head pigment fluorescence levels to age field males collected from mating swarms, and found that 25-63% of swarming males were older than 13 d. Male age may be one factor influencing the observed low levels of cytoplasmic incompatibility detected in the field.

Distribution and diversity of Wolbachia infections in Southeast Asian mosquitoes (Diptera: Culicidae).

Wolbachia are a group of intracellular inherited bacteria that infect a wide range of arthropods. They are associated with a variety of reproductive alterations in their hosts, the best known being cytoplasmic incompatability. The Wolbachia pipientis assemblage has been divided into two major groups (A and B) and 12 subgroups. We report herein the first systematic survey of Wolbachia in mosquitoes, and the first survey classifying Wolbachia infections by subgroup. Wolbachia were detected in 28.1% of 89 wild-caught mosquito species, based on a polymerase chain reaction assay using ftsZ and wsp gene primers. Infections were found in all major disease vector genera except Anopheles. Nine of the 12 Wolbachia subgroups were represented. Group B Wolbachia strains showed more phylogenetic concordance with their host taxa than group A strains. Of the 25 positive mosquito species, five were superinfected with group A bacteria strains (AA), eight were superinfected with A and B strains (AB), and one was superinfected with group B strains (BB). The widespread distribution of Wolbachia among mosquito species further supports their potential importance in the genetic control of disease vectors.

Seasonal and spatial variation in natural densovirus infection in Anopheles minimus S.L. in Thailand.

We report the first detection of a mosquito densovirus in anophelines, An. minimus species A and species C, and describe temporal and spatial variation in natural densovirus infection. A total of 814 (136 species A; 678 species C) adult mosquitos, obtained over a one year period from human biting catches at three locations in a village in western Thailand, were PCR tested for densovirus infection. Overall infection prevalence did not differ between species (15.4% species A; 14.5% species C). Infection prevalence showed significant seasonal variation. Some spatial heterogeneity in infection was also noted, with timing of peak infection prevalence varying between sites. PCR-screening of An. minimus s.l. larvae found an overall infection prevalence of 18.8%. Larval infection showed a significant positive association with rainfall recorded two months previous to larval collection. Infection in adult mosquitos showed a moderate relationship to environmental variables, but a significant negative correlation with larval infection in the previous month.

Effect of multiple micronutrient-fortified food on mild morbidity and clinical symptoms in Zambian infants: results from a randomised controlled trial.

BACKGROUND/OBJECTIVES: We aimed to assess the effects on mild morbidity of a richly micronutrient-fortified complementary/replacement food given to Zambian infants aged 6-18 months. Previous results (The Chilenje Infant Growth, Nutrition and Infection Study Team, 2010) showed an increase in the rate of hospital referral for pneumonia in the same cohort. SUBJECT/METHODS: A total of 743 six-month-old healthy Zambian infants were randomised to receive either a richly or a basal micronutrient-fortified porridge for 12 months. Mild morbidity was defined as an illness that did not cause death or require hospitalisation and was diagnosed on clinical examination at scheduled visits. RESULTS: There was no evidence of an effect of trial arm on overall mild morbidity during the study (odds ratio (OR)=1.04, 95% confidence interval (CI)=0.90, 1.20, P=0.62). Infants in the richly fortified arm had significantly more visits in which they were diagnosed with lower respiratory tract infections/pneumonia (OR=1.65, 95% CI=1.06, 2.59, P=0.03) and fewer visits in which a diagnosis of urinary tract infection was made (OR=0.43, 95% CI=0.21, 0.87, P=0.02). Maternally reported symptoms were similar between trial arms. CONCLUSION: Compared with the basal diet, the richly micronutrient-fortified food was associated with more episodes of lower respiratory infections/pneumonia diagnosed at scheduled visits, which reinforces our previously reported findings of a higher incidence in hospital referral for pneumonia.

Epidemiological and ecological characteristics of past dengue virus infection in Santa Clara, Peru.

To determine risk factors associated with dengue (DEN) virus infection among residents of Santa Clara, Peru, a rural Amazonian village near Iquitos, a cross-sectional serological, epidemiological and environmental survey was conducted. Demographic, social and behavioural information was obtained by standardized questionnaire from 1225 Santa Clara residents (61.3%) aged 5 years or older. Additional data were obtained on the environmental variables and immature mosquito species and abundance surrounding each household (n = 248). Sera that had been collected previously by the Peruvian Ministry of Health from residents were tested by an enzyme-linked immunosorbent assay (ELISA) for DEN virus IgG antibody. Antibody identity was verified as DEN by plaque reduction neutralization test. Data on individuals were analysed by univariate and multivariable methods, and independent sample t-tests. Spatial clustering was evaluated by comparing distances among DEN positive households. Overall, antibody prevalence was 29.4 % and more than doubled from the youngest to the oldest age groups, but did not differ by sex. Curiously, length of residence in Santa Clara was negatively associated with DEN virus antibodies. More frequent travel to Iquitos was positively associated with seroprevalence. Residents who obtained water from a river source rather than a local well also had significantly higher antibody prevalence. None of the environmental variables measured at each household corresponded to the patterns of antibody distribution. Of the larval mosquitoes found around residences, all were determined to be species other than Aedes. No evidence of spatial autocorrelation among antibody-positive households was detected. These results strongly suggested that recent DEN virus transmission did not occur in the village and that most infections of residents of this rural village were acquired while visiting the city of Iquitos.