Impact of Low-Frequency Human Immunodeficiency Virus Type 1 Drug Resistance Mutations on Antiretroviral Therapy Outcomes.

BACKGROUND: The association between low-frequency human immunodeficiency virus type 1 (HIV-1) drug resistance mutations (DRMs) and treatment failure (TF) is controversial. We explore this association using next-generation sequencing (NGS) methods that accurately sample low-frequency DRMs. METHODS: We enrolled women with HIV-1 in Malawi who were either antiretroviral therapy (ART) naive (cohort A), had ART failure (cohort B), or had discontinued ART (cohort C). At entry, cohorts A and C began a nonnucleoside reverse transcriptase inhibitor-based regimen and cohort B started a protease inhibitor-based regimen. We used Primer ID MiSeq to identify regimen-relevant DRMs in entry and TF plasma samples, and a Cox proportional hazards model to calculate hazard ratios (HRs) for entry DRMs. Low-frequency DRMs were defined as ≤20%. RESULTS: We sequenced 360 participants. Cohort B and C participants were more likely to have TF than cohort A participants. The presence of K103N at entry significantly increased TF risk among A and C participants at both high and low frequency, with HRs of 3.12 (95% confidence interval [CI], 1.58-6.18) and 2.38 (95% CI, 1.00-5.67), respectively. At TF, 45% of participants showed selection of DRMs while in the remaining participants there was an apparent lack of selective pressure from ART. CONCLUSIONS: Using accurate NGS for DRM detection may benefit an additional 10% of patients by identifying low-frequency K103N mutations.

Impact Of Low-Frequency HIV-1 Drug Resistance Mutations On Antiretroviral Therapy Outcomes.

BACKGROUND: The association between low-frequency HIV-1 drug resistance mutations (DRMs) and treatment failure (TF) is controversial. We explore this association using NGS methods that accurately sample low-frequency DRMs. METHODS: We enrolled women with HIV-1 in Malawi who were either ART naïve (A), had ART failure (B), or had discontinued ART (C). At entry, A and C began an NNRTI-based regimen and B started a PI-based regimen. We used Primer ID MiSeq to identify regimen-relevant DRMs in entry and TF plasma samples, and a Cox proportional hazards model to calculate hazard ratios (HRs) for entry DRMs. Low-frequency DRMs were defined as ≤ 20%. RESULTS: We sequenced 360 participants. Cohort B and C participants were more likely to have TF than Cohort A participants. The presence of K103N at entry significantly increased TF risk among A and C participants at both high and low frequency, with HR of 3.12 [1.58-6.18, 95% CI] and 2.38 [1.00-5.67, 95% CI] respectively. At TF, 45% of participants showed selection of DRMs while in the remaining participants there was an apparent lack of selective pressure from ART. CONCLUSIONS: Using accurate NGS for DRM detection may benefit an additional 10% of the patients by identifying low-frequency K103N mutations.

Three-year outcomes for women newly initiated on lifelong antiretroviral therapy during pregnancy - Malawi option B.

INTRODUCTION: Antiretroviral therapy (ART) is very effective in preventing vertical transmission of HIV but some women on ART experience different virologic, immunologic, and safety profiles. While most pregnant women are closely monitored for short-term effects of ART during pregnancy, few women receive similar attention beyond pregnancy. We aimed to assess retention in care and clinical and laboratory-confirmed outcomes over 3 years after starting ART under Malawi's Option B + program. METHODS: We conducted a prospective cohort study of pregnant women newly diagnosed with HIV who started tenofovir disoproxil fumarate/emtricitabine/efavirenz (TDF/3TC/EFV) for the first time at Bwaila Hospital in Lilongwe, Malawi between May 2015 and June 2016. Participants were followed for 3 years. We summarized demographic characteristics, pregnancy outcomes, and clinical and laboratory adverse events findings using proportions. Log-binomial regression models were used to estimate the overall risk ratios (RR) and the corresponding 95% confidence interval (CI) for the association between index pregnancy (i.e. index pregnancy vs. subsequent pregnancy) and preterm birth, and index pregnancy and low birthweight. RESULTS: Of the 299 pregnant women who were enrolled in the study, 255 (85.3%) were retained in care. There were 340 total pregnancies with known outcomes during the 36-month study period, 280 index pregnancies, and 60 subsequent pregnancies. The risks of delivering preterm (9.5% for index pregnancy and13.5% for subsequent pregnancy: RR = 0.70; 95% CI: 0.32-1.54), or low birth weight infant (9.8% for index pregnancy and 4.2% for subsequent pregnancy: RR = 2.36; 95% CI: 0.58-9.66) were similar between index and subsequent pregnancies. Perinatally acquired HIV was diagnosed in 6 (2.3%) infants from index pregnancies and none from subsequent pregnancies. A total of 50 (16.7%) women had at least one new clinical adverse event and 109 (36.5%) women had at least one incident abnormal laboratory finding. Twenty-two (7.3%) women switched to second line ART: of these 64.7% (8/17) had suppressed viral load and 54.9% (6/17) had undetectable viral load at 36 months. CONCLUSION: Most of the women who started TDF/3TC/EFV were retained in care and few infants were diagnosed with perinatally acquired HIV. Despite switching, women who switched to second line therapy continued to have higher viral loads suggesting that additional factors beyond TDF/3TC/EFV failure may have contributed to the switch. Ongoing support during the postpartum period is necessary to ensure retention in care and prevention of vertical transmission.

Factors associated with a history of treatment interruption among pregnant women living with HIV in Malawi: A cross-sectional study.

INTRODUCTION: Long-term care engagement of women on antiretroviral therapy (ART) is essential to effective HIV public health measures. We sought to explore factors associated with a history of HIV treatment interruption among pregnant women living with HIV presenting to an antenatal clinic in Lilongwe, Malawi. METHODS: We performed a cross-sectional study of pregnant women living with HIV who had a history of ART interruption presenting for antenatal care. Women were categorized as either retained in HIV treatment or reinitiating care after loss-to-follow up (LTFU). To understand factors associated with treatment interruption, we surveyed socio-demographic and partner relationship characteristics. Crude and adjusted prevalence ratios (aPR) for factors associated with ART interruption were estimated using modified Poisson regression with robust variance. We additionally present patients' reasons for ART interruption. RESULTS: We enrolled 541 pregnant women living with HIV (391 retained and 150 reinitiating). The median age was 30 years (interquartile range (IQR): 25-34). Factors associated with a history of LTFU were age <30 years (aPR 1.46; 95% CI: 1.33-1.63), less than a primary school education (aPR 1.25; CI: 1.08-1.46), initiation of ART during pregnancy or breastfeeding (aPR 1.49, CI: 1.37-1.65), nondisclosure of HIV serostatus to their partner (aPR 1.39, CI: 1.24-1.58), lack of awareness of partner's HIV status (aPR 1.41, CI: 1.27-1.60), and no contraception use at conception (aPR 1.60, CI 1.40-1.98). Access to care challenges were the most common reasons reported by women for treatment interruption (e.g., relocation, transport costs, or misplacing health documentation). CONCLUSIONS: Interventions that simplify the ART clinic transfer process, facilitate partner disclosure, and provide counseling about the importance of lifelong ART beyond pregnancy and breastfeeding should be further evaluated for improving retention in ART treatment of women living with HIV in Malawi.

Probable perinatal depression and social support among women enrolled in Malawi's Option B+ Program: A longitudinal analysis.

BACKGROUND: Malawi's PMTCT Option B+ program has expanded the reach of ART services among pregnant and breastfeeding women, but retention in lifelong HIV care remains challenging. Given that depression can undermine retention, it is important to understand how depression changes over the perinatal period, varies across treatment and retention groups, and could be buffered by social support. METHODS: Data are from an observational study conducted among women enrolled in Malawi's PMTCT Option B+ program. We used multilevel generalized linear models to estimate the odds of probable depression by time, treatment and retention group, and social support. Probable depression was assessed with the Edinburgh Postnatal Depression Scale and Patient Health Questionnaire-9. RESULTS: Of 468 women, 15% reported probable depression at antenatal enrollment and prevalence differed across newly diagnosed individuals, second line therapy users, and previous defaulters (18%, 21%, 5%, p = 0.001). Odds of probable perinatal depression decreased over time (OR per month: 0.87, 95% CI: 0.82-0.92) but were higher among those newly diagnosed (OR: 3.25, 95% CI: 1.59-6.65) and on second line therapy (OR: 3.39, 95% CI: 1.44-7.99) as compared to previous defaulters. Odds of probable postpartum depression were lower for participants with high social support (OR: 0.19, 95% CI: 0.09-0.39). LIMITATIONS: Lack of diagnostic psychiatric evaluation precludes actual diagnosis of depression. CONCLUSIONS: Probable depression varied across the perinatal period and across treatment and retention groups. Social support was protective for postpartum depression among all participants. Depression screening and provision of social support should be considered in PMTCT programs.

Locally contextualizing understandings of depression, the EPDS, and PHQ-9 among a sample of postpartum women living with HIV in Malawi.

BACKGROUND: The Edinburgh Postnatal Depression Scale (EPDS) and Patient Health Questionnaire-9 (PHQ-9) are widely used depression screening tools, yet perceptions and understandings of their questions and of depression are not well defined in cross-cultural research. METHODS: 30 postpartum women living with HIV in Malawi were recruited from a cohort study and participated in in-depth cognitive interviews. Transcripts were evaluated following an inductive approach to identify common themes. RESULTS: Participants most frequently described looking sad or different than usual, self-isolation, 'thinking too much,' and anger as key symptoms of being depressed. HIV-associated stigma was commonly identified as a cause of depression. The EPDS and PHQ-9 were generally well understood but did not capture all the important symptoms of depression that women described. Participants sometimes requested clarification or rephrasing of certain EPDS and PHQ-9 questions when asked to explain the questions' meanings in their own words, and requested rephrasing more often for EPDS questions than PHQ-9 questions. Few women believed either tool was sufficient to detect depression. LIMITATIONS: Our results may not be generalizable, but are locally contextualized. Women suffering with depression may have been more or less likely to agree to the qualitative interview depending on their comfort level discussing any current depressive symptoms. CONCLUSIONS: Researchers and practitioners who use the EPDS and PHQ-9 should be aware of the tools' limitations in their context and population. New instruments may need to be developed or adaptations to existing tools made to improve accuracy of depression screening and diagnosis in different cultural contexts.

Safety and efficacy of Option B+ ART in Malawi: few severe maternal toxicity events or infant HIV infections among pregnant women initiating tenofovir/lamivudine/efavirenz.

OBJECTIVES: Malawi's Option B+ universal antiretroviral therapy (ART) program for pregnant and breastfeeding women does not include routine laboratory monitoring. We report safety outcomes of pregnant women who initiated ART through Option B+. METHODS: We analysed 12-month data from an observational cohort study on Option B+ among women newly initiating tenofovir/lamivudine/efavirenz (TDF/3TC/EFV) at a government antenatal clinic in Lilongwe, Malawi. Proportions of women engaged in care, incidence of DAIDS grade ≥ 2 laboratory toxicity, grade ≥ 3 adverse events (AEs), viral suppression (<1000 copies/mL), birth outcomes and infant HIV infections are reported. RESULTS: At ART initiation, participants (n = 299) had a median age of 26 years (IQR 22-30), median CD4 count of 352 cells/µl (IQR 231-520) and 94% were in WHO Stage 1. We noted 76 incident DAIDS Grade ≥ 2 laboratory results among 58 women, most commonly elevated liver function tests (n = 30 events) and low haemoglobin (n = 27). No women had elevated creatinine. Clinical AEs (n = 45) were predominantly infectious diseases and Grade 3. Five participants (2%) discontinued TDF/3TC/EFV due to virologic failure (3) or toxicity (2). Twelve months after ART initiation, most women were engaged in care (89%) and had HIV RNA < 1000 copies/ml (90%). 8% of pregnancies resulted in preterm birth, 9% were low birthweight (<2500 g), and 2% resulted in infant HIV infection at 6 weeks post-delivery. CONCLUSION: Most women remained on ART and were virally suppressed 12 months after starting Option B+. Few infants contracted HIV perinatally. While some women experienced adverse laboratory events, clinical symptom monitoring is likely reasonable.

OBJECTIFS: Le programme de traitement antirétroviral (ART) universel Option B+ du Malawi pour les femmes enceintes et allaitantes n'inclut pas de suivi de routine en laboratoire. Nous rapportons les résultats en matière de sécurité des femmes enceintes qui ont commencé l'ART via l'Option B+. MÉTHODES: Nous avons analysé les données sur 12 mois d'une étude observationnelle de cohorte portant sur l'Option B+ chez des femmes initiant récemment le traitement par ténofovir/lamivudine/éfavirenz (TDF/3TC/EFV) dans une clinique prénatale du gouvernement à Lilongwe, au Malawi. Les proportions des femmes engagées dans les soins, l'incidence de DAIDS de stade ≥ 2 toxicités de laboratoire, de stade ≥ 3 événements indésirables (EI), la suppression virale (<1000 copies/mL), les résultats de naissance et l'infection infantile par le VIH sont rapportés. RÉSULTATS: A l'initiation de l'ART, les participantes (n = 299) avaient un âge médian de 26 ans (IQR 22-30), taux médian de CD4: 352 cellules/µL (IQR 231-520) et 94% étaient au stade 1 de l'OMS. Nous avons noté 76 incidents DAIDS de stade ≥ 2 résultats de laboratoire chez 58 femmes, le plus souvent, élévationdes tests de la fonction hépatique (n = 30 événements) et faible taux d'hémoglobine (n = 27). Aucune femme n'avait de créatinine élevée. Les EI cliniques (n = 45) étaient principalement des maladies infectieuses et le stade 3. Cinq participantes (2%) ont arrêté TDF/3TC/EFV en raison d'un échec virologique (n=3) ou d'une toxicité (n = 2). Douze mois après l'initiation de l'ART, la plupart des femmes suivaient des soins (89%) et avaient un ARN-VIH <1000 copies/ml (90%). 8% des grossesses ont abouti à une naissance prématurée, 9% avaient un faible poids à la naissance (<2500 g) et 2% ont résulté en une infection par le VIH chez le nourrisson à6 semaines après l'accouchement. CONCLUSION: La plupart des femmes sont restées sous ART et ont connu une suppression virale12 mois après le début de l'Option B+. Peu d'enfants ont contracté le VIH pendant la période périnatale. Bien que certaines femmes aient connu des effets adversesde laboratoire, la surveillance des symptômes cliniques est probablement raisonnable.

Prevalence of antiretroviral therapy treatment failure among HIV-infected pregnant women at first antenatal care: PMTCT Option B+ in Malawi.

BACKGROUND: In Malawi's PMTCT Option B+ program, HIV-infected pregnant women who are already receiving ART are continued on their current therapy regimen without testing for treatment failure at the first antenatal care (ANC) visit. HIV RNA screening at ANC may identify women with treatment failure and ensure that viral suppression is maintained throughout the pregnancy. METHODS: We conducted a cross-sectional study of HIV-infected pregnant women who had been receiving ART for at least 6 months at the first ANC visit under the PMTCT Option B+ program at Bwaila Hospital in Lilongwe, Malawi from June 2015 to December 2017. Poisson regression models with robust variance were used to investigate the predictors of ART treatment failure defined as viral load ≥1000 copies/ml. RESULTS: The median age of 864 women tested for ART failure was 31.1 years (interquartile range: 26.9-34.5). The prevalence of treatment failure was 7.6% (95% confidence interval (CI): 6.0-9.6). CD4 cell count (adjusted prevalence ratio (aPR) = 0.57; 95% CI: 0.50-0.65) was strongly associated with treatment failure. CONCLUSION: The low prevalence of treatment failure among women presenting for their first ANC in urban Malawi demonstrates success of Option B+ in maintaining viral suppression and suggests progress towards the last 90% of the UNAIDS 90-90-90 targets. Women failing on ART should be identified early for adherence counseling and may require switching to an alternative ART regimen.

Probable antenatal depression at antiretroviral initiation and postpartum viral suppression and engagement in care.

OBJECTIVE: To estimate the association of probable antenatal depression with postpartum HIV care engagement among pregnant women in Malawi. DESIGN: We conducted a prospective cohort study of 299 women who were initiating antiretroviral therapy (ART) through Option B+ at a government antenatal clinic in Malawi. METHODS: Probable antenatal depression was assessed on the day of ART initiation with the validated Chichewa version of the Edinburgh Postnatal Depression Scale (EPDS). We estimated crude and adjusted risk differences (RD, aRD) of visit attendance and prevalence differences (PD, aPD) of viral suppression through 12 months post-ART initiation comparing women with versus without probable antenatal depression. RESULTS: One in 10 women had probable antenatal depression. Most women were engaged in care through 12 months post-ART initiation: 85% attended all scheduled ART visits, and 81% were in care and virally suppressed. Women with and without probable antenatal depression had a comparable probability of attending all scheduled visits (RD: -0.02; 95% CI -0.16 to 0.12; aRD: -0.04; 95% CI -0.18 to 0.10), and of viral suppression (PD: -0.02; 95% CI -0.17 to 0.13; aPD: -0.01; 95% CI -0.17 to 0.15) in crude and adjusted analyses. CONCLUSION: Probable antenatal depression was not associated with engagement in HIV care through 12 months post-ART initiation. In a population with high HIV care engagement, antenatal depression may not impair HIV-related outcomes.

Prevalence and incidence of probable perinatal depression among women enrolled in Option B+ antenatal HIV care in Malawi.

BACKGROUND: Perinatal depression is a common condition of pregnancy and the postpartum period. Depression negatively affects engagement in HIV care, but systematic screening for perinatal depression is not done in most sub-Saharan African countries. Estimating the burden and timing of perinatal depression can help inform medical programs with the current scale-up of HIV care for pregnant women. METHODS: Women (n = 299) initiating antiretroviral therapy for HIV were recruited from a government antenatal clinic in Malawi in 2015-2016 into a cohort study. Probable perinatal depression was assessed at enrollment and at 6 weeks and 3, 6, and 12 months postpartum with the Edinburgh Postnatal Depression Scale (EPDS) and Patient Health Questionnaire-9 (PHQ-9). We estimated point prevalence and incidence of depression as well as concordance between EPDS and PHQ-9 scores. RESULTS: One in ten women screened positive for probable antenatal depression, whereas 1-6% screened positive postpartum. Sensitivity analyses to account for loss to follow-up suggested that postpartum depression prevalence could have ranged from 1-11%. At postpartum time points, 0-3% of participants screened positive for incident probable depression. EPDS and PHQ-9 scores were concordant for 96% of assessments during antenatal and postpartum visits. LIMITATIONS: Lack of diagnostic psychiatric evaluation precludes actual diagnosis of major depression, and social desirability bias may have contributed to low postpartum scores. CONCLUSIONS: Probable depression was more common during the antenatal period than postpartum among our participants. Given the association between depression and negative HIV outcomes, screening for depression during pregnancy should be integrated into antenatal HIV care.

Optimizing prevention of HIV mother to child transmission: Duration of antiretroviral therapy and viral suppression at delivery among pregnant Malawian women.

BACKGROUND: Effective antiretroviral therapy during pregnancy minimizes the risk of vertical HIV transmission. Some women present late in their pregnancy for first antenatal visit; whether these women achieve viral suppression by delivery and how suppression varies with time on ART is unclear. METHODS: We conducted a prospective cohort study of HIV-infected pregnant women initiating antiretroviral therapy for the first time at Bwaila Hospital in Lilongwe, Malawi from June 2015 to November 2016. Multivariable Poisson models with robust variance estimators were used to estimate risk ratios (RR) and 95% confidence intervals (CI) of the association between duration of ART and both viral load (VL) ≥1000 copies/ml and VL ≥40 copies/ml at delivery. RESULTS: Of the 252 women who had viral load testing at delivery, 40 (16%) and 78 (31%) had VL ≥1000 copies/ml and VL ≥40 copies/ml, respectively. The proportion of women with poor adherence to ART was higher among women who were on ART for ≤12 weeks (9/50 = 18.0%) than among those who were on ART for 13-35 weeks (18/194 = 9.3%). Compared to women who were on ART for ≤12 weeks, women who were on ART for 13-20 weeks (RR = 0.52; 95% CI: 0.36-0.74) or 21-35 weeks (RR = 0.26; 95% CI: 0.14-0.48) had a lower risk of VL ≥40 copies/ml at delivery. Similar comparisons for VL ≥1000 copies/ml at delivery showed decrease in risk although not significant for those on ART 13-20 weeks. CONCLUSION: Longer duration of ART during pregnancy was associated with suppressed viral load at delivery. Early ANC attendance in pregnancy to facilitate prompt ART initiation for HIV-positive women is essential in the effort to eliminate HIV vertical transmission.

Perceptions about the acceptability of assessments of HIV medication adherence in Lilongwe, Malawi and Chennai, India.

Little research exists on acceptability issues related to assessments of adherence to ART in resource-poor settings. To help prepare for two large-scale, multisite ART intervention trials, this qualitative study of individuals in Chennai, India (49 men, 11 women; 33 taking ART, 27 not) and Lilongwe, Malawi (5 men, 5 women, all taking ART) examined potential limitations of different types of adherence assessments: an adherence questionnaire, a pill diary, a pillbox, an electronic pill cap, and a medication punch card. Many participants reported that the various assessments would be acceptable. Potential limitations included issues surrounding literacy, the desire to appease one's medical provider, privacy and stigma, and "cheating." These potential limitations are similar to the limitations of these assessments in Western settings. However, the data highlight the need to consider individual patient level concerns when assessing ART adherence in different cultural settings. Innovative ways of monitoring adherence while maintaining standardization across sites are required in multisite trials.