Characterization of HIV drug resistance mutations among patients failing first-line antiretroviral therapy from a tertiary referral center in Lusaka, Zambia: Sequence Analysis of HIV DRMs in Lusaka, Zambia

In settings of resource constraint, an understanding of HIV drug resistance can guide antiretroviral therapy (ART) at switch to second-line therapy. To determine the prevalence of such HIV drug resistance mutations (HIV DRM), we used an in-house sequencing assay in the pol gene (protease and partial reverse transcriptase) in a cohort of patients suspected of failing a first-line regimen, which in Zambia comprises two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI). Our analysis cohort (n=68) was referred to the University Teaching Hospital in Lusaka from November 2009 to October 2012. Median duration on first-line ART to suspected treatment failure was 3.2 years (IQR 1.7–4.7 years). The majority of patients (95%) harbored HIV-1 subtype C virus. Analysis of reverse transcriptase revealed M184V (88%), K103N/S (32%), and Y181C/I/V (41%) DRMs, with the latter conferring reduced susceptibility to the salvage therapy candidates etravirine and rilpivirine. Three patients (5%) had major protease inhibitor (PI) resistance mutations: all three had the V82A mutation, and one patient (Clade J virus) had a concurrent M46I, Q58E, and L76V DRM. HIV-1 genotyping revealed major and minor DRMs as well as high levels of polymorphisms in subtype C isolates from patients failing first-line antiretroviral therapy. Closer monitoring of DRM mutations at first-line failure can inform clinicians about future options for salvage therapy

Patient-reported reasons for stopping care or switching clinics in Zambia: A multisite, regionally representative estimate using a multistage sampling-based approach in Zambia

BACKGROUND: Understanding patient-reported reasons for lapses of retention in human immunodeficiency virus (HIV) treatment can drive improvements in the care cascade. A systematic assessment of outcomes among a random sample of patients lost to follow-up (LTFU) from 32 clinics in Zambia to understand the reasons for silent transfers and disengagement from care was undertaken. METHODS: We traced a simple random sample of LTFU patients (\u3e90 days from last scheduled visit) as determined from clinic-based electronic medical records from a probability sample of facilities. Among patients found in person, we solicited reasons for either stopping or switching care and predictors for re-engagement. We coded reasons into structural, psychosocial, and clinic-based barriers. RESULTS: Among 1751 LTFU patients traced and found alive, 31% of patients starting antiretroviral therapy (ART) between 1 July 2013 and 31 July 2015 silently transferred or were disengaged (40% male; median age, 35 years; median CD4 level, 239 cells/μL); median time on ART at LTFU was 480 days (interquartile range, 110-1295). Among the 544 patients not in care, median prevalences for patient-reported structural, psychosocial, and clinic-level barriers were 27.3%, 13.9%, and 13.4%, respectively, and were highly variable across facilities. Structural reasons, including, relocated to a new place were mostly cited among 289 patients who silently transferred (35.5%). We found that men were less likely to re-engage in care than women (odds ratio, .39; 95% confidence interval, .22-.67; P = .001). CONCLUSIONS: Efforts to improve retention of patients on ART may need to be tailored at the facility level to address patient-reported barriers

Age at Antiretroviral Therapy Initiation Predicts Immune Recovery, Death, and Loss to Follow-Up Among HIV-Infected Adults in Urban Zambia

We analyzed the association of age at antiretroviral therapy (ART) initiation with CD4+ T cell count recovery, death, and loss to follow-up (LTFU) among HIV-infected adults in Zambia. We compared baseline characteristics of patients by sex and age at ART initiation [categorized as 16–29 years, 30–39 years, 40–49 years, 50–59 years, and 60 years and older]. We used the medication possession ratio to assess adherence and analysis of covariance to measure the adjusted change in CD4+ T cell count during ART. Using Cox proportional hazard regression, we examined the association of age with death and LTFU. In a secondary analysis, we repeated models with age as a continuous variable. Among 92,130 HIV-infected adults who initiated ART, the median age was 34 years and 6,281 (6.8%) were aged ≥50 years. Compared with 16–29 year olds, 40–49 year olds (–46 cells/mm3), 50–59 year olds (–53 cells/mm3), and 60+ year olds (–60 cells/mm3) had reduced CD4+ T cell gains during ART. The adjusted hazard ratio (AHR) for death was increased for individuals aged ≥40 years (AHR 1.25 for 40–49 year olds, 1.56 for 50–59 year olds, and 2.97 for 60+ year olds). Adherence and retention in care were poorest among 16–29 year olds but similar in other groups. As a continuous variable, a 5-year increase in age predicted reduced CD4+ T cell count recovery and increased risk of death. Increased age at ART initiation was associated with poorer clinical outcomes, while age <30 years was associated with a higher likelihood of being lost to follow-up. HIV treatment guidelines should consider age-specific recommendations

Prevalence of and factors associated with late diagnosis of HIV in Malawi, Zambia, and Zimbabwe: Results from population-based nationally representative surveys

Introduction Late diagnosis of HIV (LD) increases the risk of morbidity, mortality, and HIV transmission. We used nationally representative data from population-based HIV impact assessment (PHIA) surveys in Malawi, Zambia, and Zimbabwe (2015–2016) to characterize adults at risk of LD and to examine associations between LD and presumed HIV transmission to cohabiting sexual partners. Methods We estimated the prevalence of LD, defined as CD4 count <350 cells/μL, among adults newly diagnosed with HIV during the surveys and odds ratios for associated factors. We linked newly diagnosed adults (index cases) to their household sexual partners and calculated adjusted odds ratios for associations between LD of the index case, viral load of the index case, and duration of HIV exposure in the relationship, and the HIV status of the household sexual partner. Results Of 1,804 adults who were newly diagnosed with HIV in the surveys, 49% (882) were diagnosed late. LD was associated with male sex, older age, and almost five times the odds of having an HIV-positive household sexual partner (adjusted odds ratio [aOR], 4.65 [95% confidence interval: 2.56–8.45]). Longer duration of HIV exposure in a relationship and higher viral load of the index case were both independently associated with higher odds of having HIV-positive household sexual partners. Individuals with HIV exposure of more than 5 years had more than three times (aOR 3.42 [95% CI: 1.63–7.18]) higher odds of being HIV positive than those with less than 2 years HIV exposure. The odds of being HIV positive were increased in individuals who were in a relationship with an index case with a viral load of 400–3499 copies/mL (aOR 4.06 [95% CI 0.45–36.46]), 3,500–9,999 copies/mL (aOR 11.32 [95% CI: 4.08–31.39]), 10,000–49,999 copies/mL (aOR 17.07 [95% CI: 9.18–31.72]), and ≥50,000 copies/mL (aOR 28.41 [95% CI: 12.18–66.28]) compared to individuals who were in a relationship with an index case with a viral load of <400 copies/mL. Conclusions LD remains a challenge in Southern Africa and is strongly associated with presumed HIV transmission to household sexual partners. Our study underscores the need for earlier HIV diagnosis, particularly among men and older adults, and the importance of index testing

Initial implementation of PrEP in Zambia: health policy development and service delivery scale-up

INTRODUCTION: Daily pre-exposure prophylaxis (PrEP) for HIV prevention is highly effective, but not yet widely deployed in sub-Saharan Africa. We describe how Zambia developed PrEP health policy and then successfully implemented national PrEP service delivery. POLICY DEVELOPMENT: Zambia introduced PrEP as a key strategy for HIV prevention in 2016, and established a National PrEP Task Force to lead policy advocacy and development. The Task Force was composed of government representatives, regulatory agencies, international donors, implementation partners and civil society organisations. Following an implementation pilot, PrEP was rolled out nationally using risk-based criteria alongside a national HIV prevention campaign. NATIONAL SCALE-UP: In the first year of implementation, ending September 2018, 3626 persons initiated PrEP. By September 2019, the number of people starting PrEP increased by over sixfold to 23 327 persons at 728 sites across all ten Zambian provinces. In the first 2 years, 26 953 clients initiated PrEP in Zambia, of whom 31% were from key and priority populations. Continuation remains low at 25% and 11% at 6 and 12 months, respectively. LESSONS LEARNT: Risk-based criteria for PrEP ensures access to those most in need of HIV prevention. Healthcare worker training in PrEP service delivery and health needs of key and priority populations is crucial. PrEP expansion into primary healthcare clinics and community education is required to reach full potential. Additional work is needed to understand and address low PrEP continuation. Finally, a task force of key stakeholders can rapidly develop and implement health policy, which may serve as a model for countries seeking to implement PrEP

Nutrition and inflammation serum biomarkers are associated with 12-week mortality among malnourished adults initiating antiretroviral therapy in Zambia

<p>Abstract</p> <p>Background</p> <p>A low body mass index (BMI) at antiretroviral therapy (ART) initiation is a strong predictor of mortality among HIV-infected adults in resource-constrained settings. The relationship between nutrition and inflammation-related serum biomarkers and early treatment outcomes (e.g., less than 90 days) in this population is not well described.</p> <p>Methods</p> <p>An observational cohort of 142 HIV-infected adults in Lusaka, Zambia, with BMI under 16 kg/m²or CD4⁺lymphocyte counts of less than 50 cells/mm³, or both, was followed prospectively during the first 12 weeks of ART. Baseline and serial post-treatment phosphate, albumin, ferritin and highly sensitive C-reactive protein (hsCRP) serum levels were measured. The primary outcome was mortality.</p> <p>Results</p> <p>Lower baseline phosphate and albumin serum levels, and higher ferritin and hsCRP, were significantly associated with mortality prior to 12 weeks (p < 0.05 for all comparisons), independent of known risk factors for early ART-associated mortality in sub-Saharan Africa. The time-dependent interval change in albumin was associated with mortality after adjusting for the baseline value (AHR 0.62 [0.43, 0.89] per 5 g/L increase), but changes in the other biomarkers were not.</p> <p>Conclusions</p> <p>The predictive value of serum biomarkers for early mortality in a cohort of adults with malnutrition and advanced HIV in a resource-constrained setting was primarily driven by pre-treatment values, rather than post-ART changes. Interventions to promote earlier HIV diagnosis and treatment, address nutritional deficiencies, and identify the etiologies of increased systemic inflammation may improve ART outcomes in this vulnerable population.</p

Prevalence of nonsuppressed viral load and associated factors among HIV-positive adults receiving antiretroviral therapy in Eswatini, Lesotho, Malawi, Zambia and Zimbabwe (2015 to 2017): results from population-based nationally representative surveys.

INTRODUCTION The global target for 2020 is that ≥90% of people living with HIV (PLHIV) receiving antiretroviral therapy (ART) will achieve viral load suppression (VLS). We examined VLS and its determinants among adults receiving ART for at least four months. METHODS We analysed data from the population-based HIV impact assessment (PHIA) surveys in Eswatini, Lesotho, Malawi, Zambia and Zimbabwe (2015 to 2017). PHIA surveys are nationally representative, cross-sectional household surveys. Data collection included structured interviews, home-based HIV testing and laboratory testing. Blood samples from PLHIV were analysed for HIV RNA, CD4 counts and recent exposure to antiretroviral drugs (ARVs). We calculated representative estimates for the prevalence of VLS (viral load <1000 copies/mL), nonsuppressed viral load (NVL; viral load ≥1000 copies/mL), virologic failure (VF; ARVs present and viral load ≥1000 copies/mL), interrupted ART (ARVs absent and viral load ≥1000 copies/mL) and rates of switching to second-line ART (protease inhibitors present) among PLHIV aged 15 to 59 years who participated in the PHIA surveys in Eswatini, Lesotho, Malawi, Zambia and Zimbabwe, initiated ART at least four months before the survey and were receiving ART at the time of the survey (according to self-report or ARV testing). We calculated odds ratios and incidence rate ratios for factors associated with NVL, VF, interrupted ART, and switching to second-line ART. RESULTS We included 9200 adults receiving ART of whom 88.8% had VLS and 11.2% had NVL including 8.2% who experienced VF and 3.0% who interrupted ART. Younger age, male sex, less education, suboptimal adherence, receiving nevirapine, HIV non-disclosure, never having married and residing in Zimbabwe, Lesotho or Zambia were associated with higher odds of NVL. Among people with NVL, marriage, female sex, shorter ART duration, higher CD4 count and alcohol use were associated with lower odds for VF and higher odds for interrupted ART. Many people with VF (44.8%) had CD4 counts <200 cells/µL, but few (0.31% per year) switched to second-line ART. CONCLUSIONS Countries are approaching global VLS targets for adults. Treatment support, in particular for younger adults, and people with higher CD4 counts, and switching of people to protease inhibitor- or integrase inhibitor-based regimens may further reduce NVL prevalence

Correction: Retention and viral suppression in a cohort of HIV patients on antiretroviral therapy in Zambia: Regionally representative estimates using a multistage-sampling-based approach.

[This corrects the article DOI: 10.1371/journal.pmed.1002811.]

Estimating Loss to Follow-Up in HIV-Infected Patients on Antiretroviral Therapy: The Effect of the Competing Risk of Death in Zambia and Switzerland

BACKGROUND: Loss to follow-up (LTFU) is common in antiretroviral therapy (ART) programmes. Mortality is a competing risk (CR) for LTFU; however, it is often overlooked in cohort analyses. We examined how the CR of death affected LTFU estimates in Zambia and Switzerland. METHODS AND FINDINGS: HIV-infected patients aged ≥18 years who started ART 2004-2008 in observational cohorts in Zambia and Switzerland were included. We compared standard Kaplan-Meier curves with CR cumulative incidence. We calculated hazard ratios for LTFU across CD4 cell count strata using cause-specific Cox models, or Fine and Gray subdistribution models, adjusting for age, gender, body mass index and clinical stage. 89,339 patients from Zambia and 1,860 patients from Switzerland were included. 12,237 patients (13.7%) in Zambia and 129 patients (6.9%) in Switzerland were LTFU and 8,498 (9.5%) and 29 patients (1.6%), respectively, died. In Zambia, the probability of LTFU was overestimated in Kaplan-Meier curves: estimates at 3.5 years were 29.3% for patients starting ART with CD4 cells <100 cells/µl and 15.4% among patients starting with ≥350 cells/µL. The estimates from CR cumulative incidence were 22.9% and 13.6%, respectively. Little difference was found between naïve and CR analyses in Switzerland since only few patients died. The results from Cox and Fine and Gray models were similar: in Zambia the risk of loss to follow-up and death increased with decreasing CD4 counts at the start of ART, whereas in Switzerland there was a trend in the opposite direction, with patients with higher CD4 cell counts more likely to be lost to follow-up. CONCLUSIONS: In ART programmes in low-income settings the competing risk of death can substantially bias standard analyses of LTFU. The CD4 cell count and other prognostic factors may be differentially associated with LTFU in low-income and high-income settings