Lack of Effectiveness of Antiretroviral Therapy in Preventing HIV Infection in Serodiscordant Couples in Uganda: An Observational Study.

BACKGROUND: We examined the real-world effectiveness of ART as an HIV prevention tool among HIV serodiscordant couples in a programmatic setting in a low-income country. METHODS: We enrolled individuals from HIV serodiscordant couples aged ≥18 years of age in Jinja, Uganda from June 2009 - June 2011. In one group of couples the HIV positive partner was receiving ART as they met clinical eligibility criteria (a CD4 cell count ≤250 cells/ μL or WHO Stage III/IV disease). In the second group the infected partner was not yet ART-eligible. We measured HIV incidence by testing the uninfected partner every three months. We conducted genetic linkage studies to determine the source of new infections in seroconverting participants. RESULTS: A total of 586 couples were enrolled of which 249 (42%) of the HIV positive participants were receiving ART at enrollment, and an additional 99 (17%) initiated ART during the study. The median duration of follow-up was 1.5 years. We found 9 new infections among partners of participants who had been receiving ART for at least three months and 8 new infections in partners of participants who had not received ART or received it for less than three months, for incidence rates of 2.09 per 100 person-years (PYRs) and 2.30 per 100 PYRs, respectively. The incidence rate ratio for ART-use was 0.91 (95% confidence interval 0.31-2.70; p=0.999). The hazard ratio for HIV seroconversion associated with ART-use by the positive partner was 1.07 (95% CI 0.41-2.80). A total of 5/7 (71%) of the transmissions on ART and 6/7 (86%) of those not on ART were genetically linked. CONCLUSION: Overall HIV incidence was low in comparison to previous studies of serodiscordant couples. However, ART-use was not associated with a reduced risk of HIV transmission in this study

Effect of a Participatory Multisectoral Maternal and Newborn Intervention on Maternal Health Service Utilization and Newborn Care Practices: A Quasi-Experimental Study in Three Rural Ugandan Districts

Background: The MANIFEST study in eastern Uganda employed a participatory multisectoral approach to reduce barriers to access to maternal and newborn care services. Objectives: This study analyses the effect of the intervention on the utilization of maternal and newborn services and care practices. Methods: The quasi-experimental pre- and post-comparison design had two main components: community mobilization and empowerment, and health provider capacity building. The primary outcomes were utilization of antenatal care (ANC), delivery and postnatal care, and newborn care practices. Baseline (n = 2237) and endline (n = 1946) data were collected from women of reproductive age. The data was analysed using difference in differences (DiD) analysis and logistic regression. Results: The DiD results revealed an 8% difference in early ANC attendance (p < 0.01) and facility delivery (p < 0.01). Facility delivery increased from 66% to 73% in the intervention area, but remained unchanged in the comparison area (64% vs 63%, p < 0.01). The DiD results also demonstrated a 20% difference in clean cord care (p < 0.001) and an 8% difference in delayed bathing (p < 0.001). The intervention elements that predicted facility delivery were attending ANC four times [adjusted odds ratio (aOR) 1.42, 95% confidence interval (CI) 1.17–1.74] and saving for maternal health (aOR 2.11, 95% CI 1.39–3.21). Facility delivery and village health team (VHT) home visits were key predictors for clean cord care and skin-to-skin care. Conclusions: The multisectoral approach had positive effects on early ANC attendance, facility deliveries and newborn care practices. Community resources such as VHTs and savings are crucial to maternal and newborn outcomes and should be supported. VHT-led health education should incorporate practical measures that enable families to save and access transport services to enhance adequate preparation for birth.DFI

Evidence for Reduced Drug Susceptibility without Emergence of Major Protease Mutations following Protease Inhibitor Monotherapy Failure in the SARA Trial

Background Major protease mutations are rarely observed following failure with protease inhibitors (PI), and other viral determinants of failure to PI are poorly understood. We therefore characterized Gag-Protease phenotypic susceptibility in subtype A and D viruses circulating in East Africa following viral rebound on PIs. Methods Samples from baseline and treatment failure in patients enrolled in the second line LPV/r trial SARA underwent phenotypic susceptibility testing. Data were expressed as fold-change in susceptibility relative to a LPV-susceptible reference strain. Results We cloned 48 Gag-Protease containing sequences from seven individuals and performed drug resistance phenotyping from pre-PI and treatment failure timepoints in seven patients. For the six patients where major protease inhibitor resistance mutations did not emerge, mean fold-change EC50 to LPV was 4.07 fold (95% CI, 2.08–6.07) at the pre-PI timepoint. Following viral failure the mean fold-change in EC50 to LPV was 4.25 fold (95% CI, 1.39–7.11, p = 0.91). All viruses remained susceptible to DRV. In our assay system, the major PI resistance mutation I84V, which emerged in one individual, conferred a 10.5-fold reduction in LPV susceptibility. One of the six patients exhibited a significant reduction in susceptibility between pre-PI and failure timepoints (from 4.7 fold to 9.6 fold) in the absence of known major mutations in protease, but associated with changes in Gag: V7I, G49D, R69Q, A120D, Q127K, N375S and I462S. Phylogenetic analysis provided evidence of the emergence of genetically distinct viruses at the time of treatment failure, indicating ongoing viral evolution in Gag-protease under PI pressure. Conclusions Here we observe in one patient the development of significantly reduced susceptibility conferred by changes in Gag which may have contributed to treatment failure on a protease inhibitor containing regimen. Further phenotype-genotype studies are required to elucidate genetic determinants of protease inhibitor failure in those who fail without traditional resistance mutations whilst PI use is being scaled up globally

High rate of HIV resuppression after viral failure on first-line antiretroviral therapy in the absence of switch to second-line therapy.

In a randomized comparison of nevirapine or abacavir with zidovudine plus lamivudine, routine viral load monitoring was not performed, yet 27% of individuals with viral failure at week 48 experienced resuppression by week 96 without switching. This supports World Health Organization recommendations that suspected viral failure should trigger adherence counseling and repeat measurement before a treatment switch is considered

HIV type 1 subtype distribution, multiple infections, sexual networks and partnership histories in female sex workers in Kampala, Uganda

We investigated for the first time the subtype distribution, prevalence of multiple HIV-1 infections, sexual networks, and partnership histories in a cohort of women engaged in high-risk sexual behavior such as female sex workers (FSWs) and women employed in entertainment facilities. Viral RNA was extracted from blood samples collected from 324 HIV-1-positive women; the gp-41 and pol-IN genes were directly sequenced. Women found to have closely related viruses and those with recombinant viruses were further analyzed in the pol-IN gene by clonal sequencing to determine HIV-1 multiple infections. Individual partnership histories were used to provide information on when sex work was undertaken and where. Subtyping in both gp-41 and pol-IN was successfully done in 210/324 (64.8%) women. Subtype distribution in these two genes was 54.3% (n=114) A/A, 2.9% (n=6) C/C, 24.3% (n=51) D/D, 11.9% (n=25) A/D, 4.8% (n=10) D/A, 0.5% (n=1) C/A, 1.0% (n=2) B/A, and 0.5% (n=1) B/D. Sexual networks were identified in six pairs and one triplet of women with closely related subtype A viruses. Partnership histories showed that women having phylogenetically similar viruses had worked in the same localities. Five cases of multiple infections were confirmed: four dual infections and one triple infection. In this first molecular epidemiology study among FSWs in Kampala, subtype A was the predominant subtype. About 9% of a subgroup had multiple infections. Partnership histories and multiple infections observed in this population suggest sexual mixing of the FSWs and their clients confirming their high-risk characteristics

High rate of HIV resuppression after viral failure on first-line antiretroviral therapy in the absence of switch to second-line therapy

In a randomized comparison of nevirapine or abacavir with zidovudine plus lamivudine, routine viral load monitoring was not performed, yet 27% of individuals with viral failure at week 48 experienced resuppression by week 96 without switching. This supports World Health Organization recommendations that suspected viral failure should trigger adherence counseling and repeat measurement before a treatment switch is considered

Correction: Evidence for reduced drug susceptibility without emergence of major protease mutations following protease inhibitor monotherapy failure in the SARA Trial

[This corrects the article DOI: 10.1371/journal.pone.0137834.]

Lack of Effectiveness of Antiretroviral Therapy in Preventing HIV Infection in Serodiscordant Couples in Uganda: An Observational Study.

The study examined the real-world effectiveness of ART as an HIV prevention tool among HIV serodiscordant couples in a programmatic setting in a low-income country.Background We examined the real-world effectiveness of ART as an HIV prevention tool among HIV serodiscordant couples in a programmatic setting in a low-income country. Methods We enrolled individuals from HIV serodiscordant couples aged >18 years of age in Jinja, Uganda from June 2009 – June 2011. In one group of couples the HIV positive partner was receiving ART as they met clinical eligibility criteria (a CD4 cell count >250 cells/ μL or WHO Stage III/IV disease). In the second group the infected partner was not yet ARTeligible. We measured HIV incidence by testing the uninfected partner every three months. We conducted genetic linkage studies to determine the source of new infections in seroconverting participants. Results A total of 586 couples were enrolled of which 249 (42%) of the HIV positive participants were receiving ART at enrollment, and an additional 99 (17%) initiated ART during the study. The median duration of follow-up was 1.5 years. We found 9 new infections among partners of participants who had been receiving ART for at least three months and 8 new infections in partners of participants who had not received ART or received it for less than three months, for incidence rates of 2.09 per 100 person-years (PYRs) and 2.30 per 100 PYRs, respectively. The incidence rate ratio for ART-use was 0.91 (95% confidence interval 0.31-2.70; p=0.999). The hazard ratio for HIV seroconversion associated with ART-use by the positive partner was 1.07 (95% CI 0.41-2.80). A total of 5/7 (71%) of the transmissions on ART and 6/7 (86%) of those not on ART were genetically linked. Conclusion Overall HIV incidence was low in comparison to previous studies of serodiscordant couples. However, ART-use was not associated with a reduced risk of HIV transmission in this study.The study was funded by CIHR (Grant numbers MOP-8970, HBF-112308 and MHI-I26391) and CANFAR (Grant number 023 502)