Epigenetic aging in older people living with HIV in Eswatini: a pilot study of HIV and lifestyle factors and epigenetic aging.

BACKGROUND: People living with HIV (PLHIV) on effective antiretroviral therapy are living near-normal lives. Although they are less susceptible to AIDS-related complications, they remain highly vulnerable to non-communicable diseases. In this exploratory study of older PLHIV (OPLHIV) in Eswatini, we investigated whether epigenetic aging (i.e., the residual between regressing epigenetic age on chronological age) was associated with HIV-related parameters, and whether lifestyle factors modified these relationships. We calculated epigenetic aging focusing on the Horvath, Hannum, PhenoAge and GrimAge epigenetic clocks, and a pace of biological aging biomarker (DunedinPACE) among 44 OPLHIV in Eswatini. RESULTS: Age at HIV diagnosis was associated with Hannum epigenetic age acceleration (EAA) (ß-coefficient [95% Confidence Interval]; 0.53 [0.05, 1.00], p = 0.03) and longer duration since HIV diagnosis was associated with slower Hannum EAA (- 0.53 [- 1.00, - 0.05], p = 0.03). The average daily dietary intake of fruits and vegetables was associated with DunedinPACE (0.12 [0.03, 0.22], p = 0.01). The associations of Hannum EAA with the age at HIV diagnosis and duration of time since HIV diagnosis were attenuated when the average daily intake of fruits and vegetables or physical activity were included in our models. Diet and self-perceived quality of life measures modified the relationship between CD4+ T cell counts at participant enrollment and Hannum EAA. CONCLUSIONS: Epigenetic age is more advanced in OPLHIV in Eswatini in those diagnosed with HIV at an older age and slowed in those who have lived for a longer time with diagnosed HIV. Lifestyle and quality of life factors may differentially affect epigenetic aging in OPLHIV. To our knowledge, this is the first study to assess epigenetic aging in OPLHIV in Eswatini and one of the few in sub-Saharan Africa.

Epigenetic aging in older people living with HIV in Eswatini: a pilot study of HIV and lifestyle factors and epigenetic aging.

Background: People living with HIV (PLHIV) on effective antiretroviral therapy (ART) are living near-normal lives. Although they are less susceptible to AIDS-related complications, they remain highly vulnerable to non-communicable diseases (NCD). In this exploratory study of older PLHIV (OPLHIV) in Eswatini, we investigated whether biological aging (i.e., the difference between epigenetic age and chronological age, termed 'epigenetic age acceleration [EAA]') was associated with HIV-related parameters, and whether lifestyle factors modified these relationships. We calculated EAA focusing on the second-generation epigenetic clocks, PhenoAge and GrimAge, and a pace of aging biomarker (DunedinPACE) among 44 OPLHIV in Eswatini. Results: Among participants, the PhenoAge clock showed older epigenetic age (68 years old [63, 77]) but a younger GrimAge epigenetic age (median=56 years old [interquartile range=50, 61]) compared to the chronological age (59 years old [54, 66]). Participants diagnosed with HIV at an older age showed slower DunedinPACE (ß-coefficient [95% Confidence Interval]; -0.02 [-0.04, -0.01], p=0.002) and longer duration since HIV diagnosis was associated with faster DunedinPACE (0.02 [0.01, 0.04], p=0.002). The average daily dietary intake of fruits and vegetables was associated with faster DunedinPACE (0.12 [0.03, 0.22], p=0.01) and modified the relationship between HIV status variables (number of years living with HIV since diagnosis, age at HIV diagnosis, CD4+ T cell counts) and PhenoAge EAA, and DunedinPACE. Conclusions: Biological age is accelerated in OPLHIV in Eswatini, with those living with HIV for a longer duration at risk for faster biological aging. Lifestyle factors, especially healthier diets, may attenuate biological aging in OPLHIV. To our knowledge, this is the first study to assess biological aging in Eswatini and one of the few in sub-Saharan Africa.

"Our parents kiss in front of us": Reasons for early sexual debut among in-school youth in the Manzini Region in Eswatini.

BACKGROUND: Early sexual debut (i.e., sex before the age of 15 years), especially if it is unprotected, may increase the risk of acquiring HIV, sexually transmitted infections, and unwanted pregnancies. We investigated the reasons for early sexual debut among in-school youth in Eswatini, a setting with high HIV incidence among youth. METHODS: This was a qualitative, exploratory-descriptive study whereby data were collected from 81 sexually active in-school youth through seven focus group discussions (FGDs) in four purposively selected public high schools (two urban and two rural) in the Manzini region, Eswatini. In each school, except one, two FGDs (one for boys and one for girls) were conducted. Qualitative data were coded and analyzed thematically in Dedoose version 8.2.14. RESULTS: Nearly 40% of the participants reported having initiated sexual activity before 18 years. Six major themes emerged from the data: i) Intrapersonal factors (feeling mature, religiosity, nutritional or dietary patterns); ii) Parenting and household factors (living arrangement, lack of sexuality education, working parents, negative role-modeling from adults); iii) Peer and partner pressure (pressure from friends, threats from sexual partners, intergenerational sexual partnerships and transactional sex, testing sexual prowess, desire to fit in); iv) Contextual factors (neighborhood, location); v) Mass media (cell phone ownership, social media, and television shows or movies); and vi) Cultural factors (attending traditional ceremonies, loss of cultural norms, values, and traditions, and dress code). CONCLUSION AND RECOMMENDATIONS: The poor monitoring and negative role-modeling by elders highlight the importance of involving parents or guardians as key stakeholders when designing interventions targeting risky sexual behavior among youth. The multifaceted nature of the cited reasons for early sexual debut calls for interventions aimed at curbing risky sexual behavior to be culturally sensitive and responsive to the themes identified in this study.

HIV incidence, viremia, and the national response in Eswatini: Two sequential population-based surveys.

With the highest HIV incidence and prevalence globally, the government of Eswatini started a substantial scale-up of HIV treatment and prevention services in 2011. Two sequential large population-based surveys were conducted before and after service expansion to assess the impact of the national response. Cross-sectional, household-based, nationally representative samples of adults, ages 18 to 49 years, were sampled in 2011 and 2016. We measured HIV prevalence, incidence (recent infection based on limiting antigen ≤1.5 optical density units and HIV RNA ≥1000 copies/mL), viral load suppression (HIV RNA <1000 copies/mL among all seropositive adults) and unsuppressed viremia (HIV RNA ≥1000 copies/mL among all, regardless of HIV status) and assessed for temporal changes by conducting a trend analysis of the log ratio of proportions, using a Z statistic distribution. HIV prevalence remained stable from 2011 to 2016 [32% versus 30%, p = 0.10]. HIV incidence significantly declined 48% [2.48% versus 1.30%, p = 0.01]. Incidence remained higher among women than men [2011: 3.16% versus 1.83%; 2016: 1.76% versus 0.86%], with a smaller but significant relative reduction among women [44%; p = 0.04] than men [53%; p = 0.09]. The proportion of seropositive adults with viral load suppression significantly increased from 35% to 71% [p < .001]. The proportion of the total adult population with unsuppressed viremia decreased from 21% to 9% [p < .001]. National HIV incidence in Eswatini decreased by nearly half and viral load suppression doubled over a five-year period. Unsuppressed viremia in the total population decreased 58%. These population-based findings demonstrate the national impact of expanded HIV services in a hyperendemic country.

HIV General Population Surveys: Shedding Light on the Status of HIV Epidemics and Informing Future Actions.

ABSTRACT: Nationally representative household surveys of the general population can provide critical assessments of the status of HIV epidemics and the impact of national HIV programs. With lessons learned from earlier surveys, PEPFAR has supported HIV-focused surveys in high burden countries to measure known HIV status, access to HIV treatment, and viral suppression, and, by using novel HIV recency assays, to estimate HIV incidence. The results from the initial population-based HIV impact assessments have transformed global HIV programming, demonstrating unexpected progress in population viral suppression and the persistent burden of high HIV incidence among adolescent girls and young women. The findings highlight the importance of tailoring programs to engage men more effectively in HIV testing and treatment. The collection of manuscripts summarized in this overview of the Supplement describe the methods and selected key findings from the initial population-based HIV impact assessment surveys. Taken together, the efforts described in these manuscripts have advanced survey and laboratory capacity and guided HIV programs toward the goal of ending the global epidemic.

HIV and aging among adults aged 50 years and older on antiretroviral therapy in Eswatini.

Background: Antiretroviral therapy (ART) has decreased HIV-related morbidity and mortality and increased life expectancy of people living with HIV (PLHIV). Globally, the number of older PLHIV (OPLHIV; ≥50 years) is growing and predicted to increase substantially in coming years. In sub-Saharan Africa, where the majority of OPLHIV reside, there are limited data on the health and well-being of OPLHIV.Methods: We conducted an exploratory descriptive study that included structured interviews with 50 OPLHIV receiving ART at an outpatient HIV clinic in Eswatini and in-depth qualitative interviews (IDIs) with a sub-set of ten participants to elicit their experiences of living with HIV as an older adult, including quality of life, physical health, and mental health. Quantitative analyses were performed to obtain both descriptive statistics and cross-tabulations. A thematic analysis of IDI narratives was conducted based on three levels of the socio-ecological model to identify sub-themes and response patterns.Results: All study participants were virally suppressed. Self-reported non-communicable disease (NCD) risk factors and markers were common, with 40% (n = 20) reporting being current or former smokers, 0% consuming the recommended servings of fruits and vegetables per day, and 57% (n = 28 of 49 reporting screening) reporting having hypertension. However, the majority (88%; 44 of 50) had sufficient physical activity; most of the activity was in the work domain. Slightly more than one-third (38%; 13 of 34 tested) had a high random blood sugar level. Barriers to living with HIV were primarily structural (food insecurity, unemployment, access to transportation and health care).Conclusions: OPLHIV should be screened for NCDs, and services for NCDs should ideally be integrated with HIV services. While all participants had controlled HIV, this study highlights the need for strategies that facilitate OPLHIV's HIV service utilisation. With the increasing numbers of OPLHIV, these issues cannot be ignored.

Swaziland HIV Incidence Measurement Survey (SHIMS): a prospective national cohort study.

BACKGROUND: Swaziland has the highest national HIV prevalence worldwide. The Swaziland HIV Incidence Measurement Survey (SHIMS) provides the first national HIV incidence estimate based on prospectively observed HIV seroconversions. METHODS: A two-stage survey sampling design was used to select a nationally representative sample of men and women aged 18-49 years from 14 891 households in 575 enumeration areas in Swaziland, who underwent household-based counselling and rapid HIV testing during 2011. All individuals aged 18-49 years who resided or had slept in the household the night before and were willing to undergo home-based HIV testing, answer demographic and behavioural questions in English or siSwati, and provide written informed consent were eligible for the study. We performed rapid HIV testing and assessed sociodemographic and behavioural characteristics with use of a questionnaire at baseline and, for HIV-seronegative individuals, 6 months later. We calculated HIV incidence with Poisson regression modelling as events per person-years × 100, and we assessed covariables as predictors with Cox proportional hazards modelling. Survey weighting was applied and all models used survey sampling methods. FINDINGS: Between Dec 10, 2010, and June 25, 2011, 11 897 HIV-seronegative adults were enrolled in SHIMS and 11 232 (94%) were re-tested. Of these, 145 HIV seroconversions were observed, resulting in a weighted HIV incidence of 2·4% (95% CI 2·1-2·8). Incidence was nearly twice as high in women (3·1%; 95% CI 2·6-3·7) as in men (1·7%; 1·3-2·1, p<0·0001). Among men, partner's HIV-positive status (adjusted hazard ratio [aHR] 2·67, 1·06-6·82, p=0·040) or unknown serostatus (aHR 4·64, 2·32-9·27, p<0·0001) in the past 6 months predicted HIV seroconversion. Among women, significant predictors included not being married (aHR 2·90, 1·44-5·84, p=0·0030), having a spouse who lives elsewhere (aHR 2·66, 1·29-5·45, p=0·0078), and having a partner in the past 6 months with unknown HIV status (aHR 2·87, 1·44-5·84, p=0·0030). INTERPRETATION: Swaziland has the highest national HIV incidence in the world. In high-prevalence countries, population-based incidence measures and programmes that further expand HIV testing and support disclosure of HIV status are needed. FUNDING: President's Emergency Plan for AIDS Relief (PEPFAR) by the Centers for Disease Control and Prevention.

Changing Antiretroviral Eligibility Criteria: Impact on the Number and Proportion of Adults Requiring Treatment in Swaziland.

OBJECTIVE: Early initiation of antiretroviral treatment (ART) at CD4 cell count ≥ 500 cells per microliter reduces morbidity and mortality in HIV-infected adults. We determined the proportion of HIV-infected people with high viral load (VL) for whom transmission prevention would be an additional benefit of early treatment. DESIGN: A randomly selected subset of a nationally representative sample of HIV-infected adults in Swaziland in 2012. METHODS: Eight to 12 months after a national survey to determine adult HIV prevalence, 1067 of 5802 individuals identified as HIV-infected were asked to participate in a follow-up cross-sectional assessment. CD4 cell enumeration, VL measurements, and ART status were obtained to estimate the proportion of currently untreated adults and of the entire HIV-infected population with high VL (≥ 1000 copies/mL) whose treatment under a test-and-treat or VL threshold eligibility strategy would reduce HIV transmission. RESULTS: Of the 927 (87% of 1067) participants enrolled, 466 (50%) reported no ART use. Among them, 424 (91%) had VL ≥ 1000 copies per milliliter; of these, 148 (35%) were eligible for ART at the then existing CD4 count threshold of <350 cells per microliter; an additional 107 (25%) were eligible with expanded CD4 criterion of <500 cells per microliter; and 169 (40%) remained ART ineligible. Thus, 36% of the 466 currently untreated and 18% of the total 927 had high VL yet remained ART ineligible under a CD4 criterion of <500 cells per microliter. CONCLUSIONS: A test-and-treat or VL threshold for treatment eligibility is necessary to maximize the HIV transmission prevention benefits of ART.

Recent HIV prevalence trends among pregnant women and all women in sub-Saharan Africa: implications for HIV estimates.

OBJECTIVES: National population-wide HIV prevalence and incidence trends in sub-Saharan Africa (SSA) are indirectly estimated using HIV prevalence measured among pregnant women attending antenatal clinics (ANC), among other data. We evaluated whether recent HIV prevalence trends among pregnant women are representative of general population trends. DESIGN: Serial population-based household surveys in 13 SSA countries. METHODS: We calculated HIV prevalence trends among all women aged 15-49 years and currently pregnant women between surveys conducted from 2003 to 2008 (period 1) and 2009 to 2012 (period 2). Log-binomial regression was used to test for a difference in prevalence trend between the two groups. Prevalence among pregnant women was age-standardized to represent the age distribution of all women. RESULTS: Pooling data for all countries, HIV prevalence declined among pregnant women from 6.5 [95% confidence interval (CI) 5.3-7.9%] to 5.3% (95% CI 4.2-6.6%) between periods 1 and 2, whereas it remained unchanged among all women at 8.4% (95% CI 8.0-8.9%) in period 1 and 8.3% (95% CI 7.9-8.8%) in period 2. Prevalence declined by 18% (95% CI -9-38%) more in pregnant women than nonpregnant women. Estimates were similar in Western, Eastern, and Southern regions of SSA; none were statistically significant (P>0.05). HIV prevalence decreased significantly among women aged 15-24 years while increasing significantly among women 35-49 years, who represented 29% of women but only 15% of pregnant women. Age-standardization of prevalence in pregnant women did not reconcile the discrepant trends because at older ages prevalence was lower among pregnant women than nonpregnant women. CONCLUSION: As HIV prevalence in SSA has shifted toward older, less-fertile women, HIV prevalence among pregnant women has declined more rapidly than prevalence in women overall. Interpretation of ANC prevalence data to inform national HIV estimates should account for both age-specific fertility patterns and HIV-related sub-fertility.

Poor performance of the determine HIV-1/2 Ag/Ab combo fourth-generation rapid test for detection of acute infections in a National Household Survey in Swaziland.

Fourth-generation HIV rapid tests (RTs) claim to detect both p24 antigen (Ag) and HIV antibodies (Ab) for early identification of acute infections, important for targeting prevention and reducing HIV transmission. In a nationally representative household survey in Swaziland, 18,172 adults, age 18 to 49 years, received home-based HIV rapid testing in 2010 and 2011. Of the 18,172 individuals, 5,822 (32.0%) were Ab positive (Ab(+)) by the Determine HIV-1/2 Ab/Ab combo test, and 5,789 (99.4%) of those were confirmed to be reactive in the Uni-Gold test. Determine combo identified 12 individuals as having acute infections (Ag(+)/Ab negative [Ab(-)]); however, none had detectable HIV-1 RNA and 8 of 12 remained HIV negative at their 6-week follow-up visit (4 were lost to follow-up). All RT-nonreactive samples were pooled and tested by nucleic acid amplification testing (NAAT) to identify acute infections. NAAT identified 13 (0.1%) of the 12,338 HIV antibody-negative specimens as HIV RNA positive, with RNA levels ranging from 300 to >10,000,000 copies/ml. However, none of them were Ag(+) by Determine combo. Follow-up testing of 12 of the 13 NAAT-positive individuals at 6 months demonstrated 12 seroconversions (1 individual was lost to follow-up). Therefore, the Determine combo test had a sensitivity of 0% (95% confidence interval, 0 to 28) and positive predictive value of 0% for the detection of acute infections. The ability of the 4th-generation Determine combo to detect antigen was very poor in Swaziland. Thus, the Determine combo test does not add any value to the current testing algorithm; rather, it adds additional costs and complexity to HIV diagnosis. The detection of acute HIV infections may need to rely on other testing strategies.

Integration of HIV and maternal healthcare in a high HIV-prevalence setting: analysis of client flow data over time in Swaziland.

OBJECTIVE: Maternal and child health (MCH) care may provide an entry point for HIV services in high HIV-prevalence settings. Our objective was to assess integration of HIV with MCH services in public sector facilities in Swaziland. DESIGN: In 2009, 2010 and 2012, client flow assessments (CFAs) were conducted over 5 days in the MCH units of eight government facilities, purposively selected as intervention or comparison sites. PARTICIPANTS: 8263 MCH visits with female clients were tracked: 3261 in 2009, 2086 in 2010 and 2916 in 2012. INTERVENTION: Activities and resources to strengthen integration of HIV services into postnatal care (PNC), 2009-2010. MAIN OUTCOME MEASURES: The proportion of all visits in which an HIV/sexually transmitted infection (STI) testing, counselling or treatment was received together with an MCH service; the proportion of all visits in which a client receives HIV counselling. RESULTS: Across facilities, the proportion of visits in which HIV/STI and MCH services were received varied considerably, for example, from 9% to 49% in 2009. HIV/STI services were integrated most frequently with child health (CH), antenatal care (ANC) and family planning (FP)-the most common reasons for women's attendance-and least often with PNC and cervical screening (CS). There was no meaningful difference in integration over time by design group and considerable heterogeneity across facilities. Receipt of integrated services increased in one intervention and two comparison facilities, where HIV counselling also rose, and fell in one intervention and two comparison facilities. CONCLUSIONS: Provision of HIV/STI services with MCH care occurred at all facilities, yet relatively few women receive integrated services. Increases in integration were driven by increases in HIV counselling, while sharp declines in some facilities indicate that integration is difficult to sustain. Opportunities for intensifying HIV integration lie with ANC, CH and FP, while HIV-PNC integration will remain limited until more women attend PNC. TRIAL REGISTRATION NUMBER: Current Controlled Trials NCT01694862.

Recent patterns in population-based HIV prevalence in Swaziland.

BACKGROUND: The 2011 Swaziland HIV Incidence Measurement Survey (SHIMS) was conducted as part of a national study to evaluate the scale up of key HIV prevention programs. METHODS: From a randomly selected sample of all Swazi households, all women and men aged 18-49 were considered eligible, and all consenting adults were enrolled and received HIV testing and counseling. In this analysis, population-based measures of HIV prevalence were produced and compared against similarly measured HIV prevalence estimates from the 2006-7 Swaziland Demographic and Health. Also, measures of HIV service utilization in both HIV infected and uninfected populations were documented and discussed. RESULTS: HIV prevalence among adults aged 18-49 has remained unchanged between 2006-2011 at 31-32%, with substantial differences in current prevalence between women (39%) and men (24%). In both men and women, between since 2006-7 and 2011, prevalence has fallen in the young age groups and risen in the older age groups. Over a third (38%) of the HIV-infected population was unaware of their infection status, and this differed markedly between men (50%) and women (31%). Of those aware of their HIV-positive status, a higher percentage of men (63%) than women (49%) reported ART use. CONCLUSIONS: While overall HIV prevalence remains roughly constant, age-specific changes strongly suggest both improved survival of the HIV-infected and a reduction in new HIV infections. Awareness of HIV status and entry into ART services has improved in recent years but remains too low. This study identifies opportunities to improve both HIV preventive and care services in Swaziland.

Scale-up of HIV treatment through PEPFAR: a historic public health achievement.

Since its inception in 2003, the US President's Emergency Plan for AIDS Relief (PEPFAR) has been an important driving force behind the global scale-up of HIV care and treatment services, particularly in expansion of access to antiretroviral therapy. Despite initial concerns about cost and feasibility, PEPFAR overcame challenges by leveraging and coordinating with other funders, by working in partnership with the most affected countries, by supporting local ownership, by using a public health approach, by supporting task-shifting strategies, and by paying attention to health systems strengthening. As of September 2011, PEPFAR directly supported initiation of antiretroviral therapy for 3.9 million people and provided care and support for nearly 13 million people. Benefits in terms of prevention of morbidity and mortality have been reaped by those receiving the services, with evidence of societal benefits beyond the anticipated clinical benefits. However, much remains to be accomplished to achieve universal access, to enhance the quality of programs, to ensure retention of patients in care, and to continue to strengthen health systems.