Effects of HIV infection and ART on phenotype and function of circulating monocytes, natural killer, and innate lymphoid cells.

HIV infection causes upregulation of markers of inflammation, immune activation and apoptosis of host adaptive, and innate immune cells particularly monocytes, natural killer (NK) and innate lymphoid cells (ILCs). Although antiretroviral therapy (ART) restores CD4 T-cell counts, the persistent aberrant activation of monocytes, NK and ILCs observed likely contributes to the incomplete recovery of T-cell effector functions. A better understanding of the effects of HIV infection and ART on the phenotype and function of circulating monocytes, NK, and ILCs is required to guide development of novel therapeutic interventions to optimize immune recovery

Low prevalence of Plasmodium falciparum antigenaemia among asymptomatic HAART-treated adults in an urban cohort in Uganda

<p>Abstract</p> <p>Background</p> <p>Presumptive treatment of malaria is common practice in malaria endemic resource-limited settings. With the changing epidemiology of malaria and the introduction of artemisinin-based combination therapy (ACT), there is increasing need for parasite-based malaria case management to prevent unnecessary use of anti-malarial medicines, improve patient care in parasite-positive patients and identify parasite-negative patients in whom another diagnosis must be sought. Although parasitological confirmation by microscopy or alternatively by malaria rapid diagnostic tests (RDTs) is recommended in all patients suspected of malaria before treatment, gaps remain in the implementation of this policy in resource-limited settings. There is need to evaluate the use of RDTs among highly active anti-retroviral therapy (HAART)-treated people living with HIV (PLHIV).</p> <p>Methods</p> <p>Within an urban prospective observational research cohort of 559 PLHIV initiated on HAART and cotrimoxazole prophylaxis between April, 2004 and April, 2005, 128 patients with sustained HIV-RNA viral load < 400 copies/ml for four years were evaluated, in a cross-sectional study, for asymptomatic malaria infection using a histidine-rich protein-2 (HRP-2) RDT to detect <it>Plasmodium falciparum </it>antigen in peripheral blood. Patients with positive RDT results had microscopy performed to determine the parasite densities and were followed for clinical signs and symptoms during the subsequent six months.</p> <p>Results</p> <p>Of the 128 asymptomatic patients screened, only 5 (4%) had asymptomatic <it>P. falciparum </it>antigenaemia. All the patients with positive HRP2 RDT results showed malaria parasites on thick film with parasite densities ranging from 02-15 malaria parasites per high power field. None of the patients with positive RDT results reported signs and symptoms of malaria infection during the subsequent six months.</p> <p>Conclusions</p> <p>In an urban area of low to moderate stable malaria transmission, there was low HRP2 P. <it>falciparum </it>antigenaemia among PLHIV after long-term HAART and cotrimoxazole prophylaxis. Parasite-based malaria diagnosis (PMD) is recommended among PLHIV that are on long-term anti-retroviral therapy. RDTs should be utilized to expand PMD in similar settings where microscopy is unavailable.</p

Sub-optimal CD4 reconstitution despite viral suppression in an urban cohort on Antiretroviral Therapy (ART) in sub-Saharan Africa: Frequency and clinical significance

<p>Abstract</p> <p>Background</p> <p>A proportion of individuals who start antiretroviral therapy (ART) fail to achieve adequate CD4 cell reconstitution despite sustained viral suppression. We determined the frequency and clinical significance of suboptimal CD4 reconstitution despite viral suppression (SO-CD4) in an urban HIV research cohort in Kampala, Uganda</p> <p>Methods</p> <p>We analyzed data from a prospective research cohort of 559 patients initiating ART between 04/04–04/05. We described the patterns of SO-CD4 both in terms of:- I) magnitude of CD4 cell increase (a CD4 count increase < 50 CD4 cells/μl at 6 months, <100 cells/μl at 12 months; and <200 cells/μl at 24 months of ART) and II) failure to achieve a CD4 cell count above 200 cells/μl at 6,12 and 24 months of ART. Using criteria I) we used logistic regression to determine the predictors of SO-CD4. We compared the cumulative risk of clinical events (death and/or recurrent or new AIDS-defining illnesses) among patients with and without SO-CD4.</p> <p>Results</p> <p>Of 559 patients initiating ART, 386 (69%) were female. Median (IQR) age and baseline CD4 counts were 38 yrs (33–44) and 98 cells/μl (21–163) respectively; 414 (74%) started a d4T-based regimen (D4T+3TC+NVP) and 145 (26%) a ZDV-based regimen (ZDV+3TC+EFV). After 6, 12 and 24 months of ART, 380 (68%), 339 (61%) and 309 (55%) had attained and sustained HIV-RNA viral suppression. Of these, 78 (21%), 151 (45%) and 166 (54%) respectively had SO-CD4 based on criteria I), and 165(43%), 143(42%) and 58(19%) respectively based on criteria II). With both criteria combined, 56 (15%) and 129 (38%) had SO-CD4 at 6 and 12 months respectively. A high proportion (82% and 58%) of those that had SO-CD4 at 6 months (using criteria I) maintained SO-CD4 at 12 and 24 months respectively. There were no statistically significant differences in the incidence of clinical events among patients with [19/100PYO (12–29)] and without SO-CD4 [23/100PYO (19–28)].</p> <p>Conclusion</p> <p>Using criteria I), the frequency of SO-CD4 was 21% at 6 months. Majority of patients with SO-CD4 at 6 months maintained SO-CD4 up to 2 years. We recommend studies of CD4 T-cell functional recovery among patients with SO-CD4.</p

Short report: knowledge and perceptions of health workers that strengthen adherence for paediatric and adolescent clients on the intensive adherence counselling program in Kampala, Uganda: a qualitative study.

BACKGROUND: Health care workers (HWs) support HIV positive children and adolescents with detectable HIV viral loads on the intensive adherence counselling (IAC) program to achieve viral suppression through individual adherence counselling. Low re-suppression rates of 23% showed low program effectiveness in fifteen public health facilities. OBJECTIVES: We set out to determine the knowledge and perceptions of HWs that support this program to improve its effectiveness. METHODS: We conducted a qualitative study where five HWs that oversee clinical care for children on ART were interviewed about the program. Data on their knowledge of the program, and perceptions on why it was not effective was collected. Thematic analysis using the inductive approach was used. Transcripts were read, coded and emergent themes determined. RESULTS: Five HWs participated and all were knowledgeable about the program. Two themes emerged as barriers to IAC program effectiveness, patient factors and health system factors. Patient factors were failure to attend appointments, failure to change adherence practices, and lack of consent. Health system factors were work overload, delay in getting results and drug stock outs. CONCLUSIONS: HWs are knowledgeable about the IAC program and client specific barriers should be addressed to improve viral suppression for children

Acceptability and Predictors of Uptake of Anti-retroviral Pre-exposure Prophylaxis (PrEP) Among Fishing Communities in Uganda: A Cross-Sectional Discrete Choice Experiment Survey.

We used a discrete choice experiment to assess the acceptability and potential uptake of HIV pre-exposure prophylaxis (PrEP) among 713 HIV-negative members of fishing communities in Uganda. Participants were asked to choose between oral pill, injection, implant, condoms, vaginal ring (women), and men circumcision. Product attributes were HIV prevention effectiveness, sexually transmitted infection (STI) prevention, contraception, waiting time, and secrecy of use. Data were analysed using mixed multinomial logit and latent class models. HIV prevention effectiveness was viewed as the most important attribute. Both genders preferred oral PrEP. Women least preferred the vaginal ring and men the implant. Condom use was predicted to decrease by one third among men, and not to change amongst women. Oral PrEP and other new prevention technologies are acceptable among fishing communities and may have substantial demand. Future work should explore utility of multiple product technologies that combine contraception with HIV and other STI prevention

Short report: knowledge and perceptions of health workers that strengthen adherence for paediatric and adolescent clients on the intensive adherence counselling program in Kampala, Uganda: a qualitative study

Background: Health care workers (HWs) support HIV positive children and adolescents with detectable HIV viral loads on the intensive adherence counselling (IAC) program to achieve viral suppression through individual adherence counselling. Low re-suppression rates of 23% showed low program effectiveness in fifteen public health facilities. Objectives: We set out to determine the knowledge and perceptions of HWs that support this program to improve its effectiveness. Methods: We conducted a qualitative study where five HWs that oversee clinical care for children on ART were interviewed about the program. Data on their knowledge of the program, and perceptions on why it was not effective was collected. Thematic analysis using the inductive approach was used. Transcripts were read, coded and emergent themes determined. Results: Five HWs participated and all were knowledgeable about the program. Two themes emerged as barriers to IAC program effectiveness, patient factors and health system factors. Patient factors were failure to attend appointments, failure to change adherence practices, and lack of consent. Health system factors were work overload, delay in getting results and drug stock outs. Conclusions: HWs are knowledgeable about the IAC program and client specific barriers should be addressed to improve viral suppression for children

Low HIV viral suppression rates following the intensive adherence counseling (IAC) program for children and adolescents with viral failure in public health facilities in Uganda

BACKGROUND: The UNAIDS 90-90-90 strategy clearly stipulates that 90% of all people on antiretroviral therapy (ART) should have a suppressed viral load. Intensified adherence counselling (IAC) was recently recommended by WHO to improve viral suppression among ART-treated paediatric and adolescent clients with virological failure. This paper describes the implementation and outcomes of IAC in the first year of implementation in a public ART program, to inform strategic interventions to reach the "third 90" among children. METHODS: A retrospective chart review was conducted for all children aged 9 months to 19 years with HIV viral loads (VL) ≥ 1000 copies/ml at 15 public health facilities from June 2015-December 2016. Data on initial VL test results, IAC sessions, repeat VL test results, and ART regimen switch were abstracted and analysed for completion of IAC and viral suppression after IAC. RESULTS: A total of 449 children had a detectable viral load above 1000 copies/ml, after an average of 3.5 years (SD 5.8) years of ART. 192 (43%) were 10-20 years of age, and 320 (71%) were receiving Nevirapine-based ART regimen. Out of 345 (77%) who completed the recommended three IAC sessions, 62 (23%) achieved viral suppression following IAC. The mean time from 1st to 3rd IAC session was 113 (SD 153) days and 172 (50%) of the children had completed the three sessions within 200 days. CONCLUSION: Suppression rates were low among ART-treated children with virological failure that completed the recommended three IAC sessions. As we move towards having 90% of ART-treated children and adolescents achieve and maintain viral suppression, there is need to re-evaluate the implementation of IAC among children and adolescents to consider both psychosocial and biological factors such as resistance testing for those with multiple detectable viral loads

Aberrant natural killer (NK) cell activation and dysfunction among ART-treated HIV-infected adults in an African cohort.

BACKGROUND: We examined NK cell phenotypes and functions after seven years of ART and undetectable viral loads (<50 copies/ml) with restored CD4 T-cell counts (≥500 cells/μl) and age-matched healthy-HIV-uninfected individuals from the same community. METHODS: Using flow-cytometry, NK cell phenotypes were described using lineage markers (CD56+/-CD16+/-). NK cell activation was determined by expression of activation receptors (NKG2D, NKp44 and NKp46) and activation marker CD69. NK cell function was determined by CD107a, granzyme-b, and IFN-gamma production. RESULTS: CD56 dim and CD56 bright NK cells were lower among ART-treated-HIV-infected than among age-matched-HIV-negative individuals; p = 0.0016 and p = 0.05 respectively. Production of CD107a (P = 0.004) and Granzyme-B (P = 0.005) was lower among ART-treated-HIV-infected relative to the healthy-HIV-uninfected individuals. NKG2D and NKp46 were lower, while CD69 expression was higher among ART-treated-HIV-infected than healthy-HIV-uninfected individuals. CONCLUSION: NK cell activation and dysfunction persisted despite seven years of suppressive ART with "normalization" of peripheral CD4 counts

Innate lymphoid cell dysfunction during long-term suppressive antiretroviral therapy in an African cohort

BACKGROUND: Innate lymphoid cells (ILC) are lymphoid lineage innate immune cells that do not mount antigen-specific responses due to their lack of B and T-cell receptors. ILCs are predominantly found at mucosal surfaces, as gatekeepers against invading infectious agents through rapid secretion of immune regulatory cytokines. HIV associated destruction of mucosal lymphoid tissue depletes ILCs, among other immune dysfunctions. Studies have described limited restoration of ILCs during the first three years of combined antiretroviral therapy (cART). Little is known about restoration of ILCs during long-term cART, particularly in sub-Saharan Africa which hosts increasing numbers of adults with at least a decade of cART. RESULTS: We examined phenotypes and function of ILCs from peripheral blood mononuclear cells after 12 years of suppressive cART. We report that ILC1 frequencies (T-BET + CD127 + and CD161 +) were higher in cART-treated HIV-infected relative to age-matched health HIV-negative adults; P = 0.04 whereas ILC precursors (ILCP) were comparable in the two groups (P = 0.56). Interferon gamma (IFN-γ) secretion by ILC1 was higher among cART-treated HIV-infected relative to HIV-negative adults (P = 0.03). CONCLUSION: HIV associated alteration of ILC persisted during cART and may likely affect the quality of host innate and adaptive immune responses during long-term cART

Career development for infection and immunity research in Uganda: a decade of experience from the Makerere University – Uganda Virus Research Institute research and training programme

Background: The Makerere University/Uganda Virus Research Institute (UVRI) Centre of Excellence for Infection & Immunity Research and Training (MUII) is a collaborative programme supporting excellence in Infection and Immunity (I&I) research in Uganda. Set up in 2008, MUII aims to produce internationally competitive Ugandan and East African I&I research leaders, and develop human and infrastructural resources to support research and training excellence. We undertook an internal evaluation of MUII’s achievements, challenges and lessons learned between 08-2008 and 12-2019, to inform programmes seeking to build Africa’s health research expertise. Methods: : Quantitative data were abstracted from programme annual reports. Qualitative data were obtained in 03-04/2019: a cross-sectional evaluation was undertaken among a purposefully selected representative sample of 27 trainees and two programme staff. Qualitative data was analysed according to pre-determined themes of achievements, challenges, lessons learned and recommendations for improvement. Results: : By 12-2019, MUII had supported 68 fellowships at master’s-level and above (50% female: 23 Masters, 27 PhD, 15 post-doctoral, three group-leaders) and over 1,000 internships. Fellows reported career advancement, mentorship by experts, and improved research skills and outputs. Fellows have published over 300 papers, secured grants worth over £20m, established over 40 international collaborations, and taken on research and academic leadership positions in the country. Key lessons were: i) Efficient administration provides a conducive environment for high quality research; ii) Institutions need supportive policies for procurement, including provisions for purchases of specific biological research reagents from international manufacturers; iii) Strong international and multi-disciplinary collaboration provides a critical mass of expertise to mentor researchers in development; and iv) Mentorship catalyses young scientists to progress from graduate trainees to productive academic researchers, relevant to society’s most pressing health challenges. Conclusions: : Sustainable academic productivity can be achieved through efficient operational support, global collaboration and mentorship to provide solutions to Africa’s health challenges