The impact of HIV infection on clinical presentation and mortality among persons with hepatocellular carcinoma in Kampala, Uganda.

BACKGROUND: HIV infection is associated with more rapid progression of some comorbidities. This study assessed the impact of HIV-infection on the presentation and outcome of HCC. METHODS: HCC patients attending the Mulago National Referral Hospital in Uganda were enrolled into a natural history study of HCC between March 2015 and February 2019. Standardized methods were used to collect clinical, ultrasound and laboratory data at enrolment. HCC cases were confirmed and enrolled based on a combination of clinical, ultrasound, tumor marker and pathology data. Follow-up contact was made at one, three, six, and twelve months post-enrolment to determine vital status. Symptoms and signs at diagnosis and subsequent survival were compared by HIV status. Kaplan Meier curves were used to assess HCC survival. RESULTS: Of 441 persons with HCC, 383 (87.0%) died within 12 months following HCC diagnosis. The median (IQR) survival was 42 (20, 106) days. HIV infection was present in 79 (18%) cases. After adjusting for baseline demographic and clinical characteristics, HIV infection was associated with increased mortality but only among those with severe HIV-associated immunosuppression (CD4 count < 200 cells per cubic milliliter), aHR (95% C) = 2.12 (1.23-3.53), p = 0.004, and not among PLWH with ≥ 200 CD4 cells per cubic milliliter, aHR (95% C) = 1.15 (0.82-1.60), p = 0.417. CONCLUSION: Among relatively young Ugandans, HCC is a devastating disease with rapid mortality that is especially rapid among people living with HIV(PLWH). HIV was associated with slightly higher mortality, notably among PLWH with lower CD4 cell counts. As a substantial majority of PLWH diagnosed with HCC were engaged in HIV care, further investigation should determine the effectiveness of incorporating screening and early identification of HCC among high-risk individuals into existing HIV care programs. Concurrent with growing access to curative localized treatment for HCC in sub-Saharan Africa, leveraging HIV care infrastructure affords opportunities for earlier HCC intervention.

Correction to: Hepatitis B virus perceptions and health seeking behaviors among pregnant women in Uganda: implications for prevention and policy.

In the original publication of this article [1], some values are missing in the Figure 1, Figure 2 and Figure 3. These errors were introduced during typesetting; thus the publisher apologizes for this error. Additionally, the original manuscript has also been updated to amend this error. The correct figures are shown below.

Hepatitis B virus perceptions and health seeking behaviors among pregnant women in Uganda: implications for prevention and policy.

BACKGROUND: With most countries in sub-Saharan Africa (SSA) lagging behind schedule to implement a comprehensive viral hepatitis elimination strategy, several barriers to accurate information and hepatitis B virus (HBV) services still exist, that are unique to different regions. In an obstetric population of a high HBV burden SSA setting without antenatal HBV services, we systematically evaluated perceptions and prevention behavioral intentions in relation to HBV and liver cancer. METHODS: Eligible consenting pregnant women were recruited from public health care facilities in the central and northern regions of Uganda, between October 2016 and December 2017. Standardized procedures and instruments based on the health belief model and theory of planned behavior were used to collect data on socio-demographic characteristics, HBV perceptions and behavioral intentions. Descriptive analysis using Chi-square tests was done to obtain distribution of respondents by levels of perceived risk of HBV and liver cancer for themselves, their child under 5 years and their spouse. Modified Poisson regression analyses were used to evaluate relationships between perception variables and different behavioral outcomes (intention to screen, vaccinate and treat HBV). RESULTS: Perceived risk (PRR = 0.95(0.90-1.00), p = 0.055) was inversely associated with intention to screen for HBV. Conversely, perceived self-efficacy showed a consistent association with intention to screen for HBV (PRR = 1.18(1.10-1.23) p = 0.005), to vaccinate (PRR = 1.20(1.05-1.36) p = 0.006) and to seek treatment for HBV (PRR = 1.40(1.18-1.67) p < 0.001). Women from the north, compared to the central region (PRR = 1.76 (1.13-2.72) p = 0.012), and those who self-identified as Catholic (PRR = 1.85 (0.99-3.56) p = 0.056), and as Protestant, (PRR = 2.22 (1.22-4.04) p = 0.002), were more likely to have higher perceived self-efficacy, compared to Muslims. Age and education were not related to perceived self-efficacy. CONCLUSION: Women in both regions hold incorrect perceptions of HBV and liver cancer risk, with women from the central reporting higher perceived risk than those from the north. High perceived self-efficacy influenced intention to participate in HBV prevention. Programs and policies geared towards enhancing HBV prevention in this sub-population may consider socio-cultural factors observed to influence prevention behaviors. These findings may guide HBV interventions aimed at improving capacity to seek HBV prevention services, thereby promoting HBV micro-elimination in this sub-population.

What is new in perinatal HIV prevention?

PURPOSE OF REVIEW: The purpose of this review is to describe recent clinical trial, laboratory and observational findings that highlight both the progress that can be achieved in elimination of new pediatric infections in international clinical trial settings among HIV-infected breastfeeding women while also describing recent safety concerns related to currently used antiretroviral regimens. The article will also address the ongoing adherence challenges for HIV-infected mothers in taking their antiretroviral drugs. This information is timely and relevant as new regimens are being considered for both prevention of mother-to-child transmission (PMTCT) of HIV and HIV treatment options worldwide. RECENT FINDINGS: The main themes described in this article include both efficacy of different antiretroviral therapy (ART) regimens currently being rolled out internationally for PMTCT as well as safety findings from recent research including a large multisite international trial, PROMISE. SUMMARY: The findings from the IMPAACT PROMISE trial as well as other recent trial and observational findings suggest that while progress has been steady in reducing PMTCT worldwide, the goal of virtual elimination of pediatric HIV worldwide will require careful attention to optimizing safety of new regimens which are less dependent on maternal daily ART adherence and safer in preventing certain toxicities.

Unintended pregnancy and contraception use among African women living with HIV: Baseline analysis of the multi-country US PEPFAR PROMOTE cohort.

BACKGROUND: About 90% of unintended pregnancies are attributed to non-use of effective contraception-tubal ligation, or reversible effective contraception (REC) including injectables, oral pills, intra-uterine contraceptive device (IUCD), and implant. We assessed the prevalence of unintended pregnancy and factors associated with using RECs, and Long-Acting-Reversible-Contraceptives (LARCs)-implants and IUCDs, among women living with HIV (WLHIV) receiving antiretroviral therapy (ART). METHODS: We conducted cross-sectional analyses of the US-PEPFAR PROMOTE study WLHIV on ART at enrollment. Separate outcome (REC and LARC) modified-Poisson regression models were used to estimate prevalence risk ratio (PRR) and corresponding 95% confidence interval (CI). RESULTS: Of 1,987 enrolled WLHIV, 990 (49.8%) reported their last/current pregnancy was unintended; 1,027/1,254 (81.9%) non-pregnant women with a potential to become pregnant reported current use of effective contraception including 215/1,254 (17.1%) LARC users. Compared to Zimbabwe, REC rates were similar in South Africa, aPRR = 0.97 (95% CI: 0.90-1.04), p = 0.355, lower in Malawi, aPRR = 0.84 (95% CI: 0.78-0.91), p<0.001, and Uganda, 0.82 (95% CI: 0.73-0.91), p<0.001. Additionally, REC use was independently associated with education attained, primary versus higher education, aPRR = 1.10 (95% CI: 1.02-1.18), p = 0.013; marriage/stable union, aPRR = 1.10 (95% CI: 1.01-1.21), p = 0.039; no desire for another child, PRR = 1.10 (95% CI: 1.02-1.16), p = 0.016; infrequent sex (none in the last 3 months), aPRR = 1.24 (95% CI: 1.15-1.33), p<0001; and controlled HIV load (≤ 1000 copies/ml), PRR = 1.10 (95% CI: 1.02-1.19), p = 0.014. LARC use was independently associated with country (Zimbabwe ref: South Africa, PRR = 0.39 (95% CI: 0.26-0.57), p<0.001; Uganda, PRR = 0.65 (95% CI: 0.42-1.01), p = 0.054; and Malawi, aPRR = 0.87 (95% CI: 0.64-1.19), p = 0.386; HIV load (≤ 1000 copies/ml copies/ml), aPRR=1.73 (95% CI: 1.26-2.37), p<0.001; and formal/self-employment, aPRR = 1.37 (95% CI: 1.02-1.91), p = 0.027. CONCLUSIONS: Unintended pregnancy was common while use of effective contraception methods particularly LARCs was low among these African WLHIV. HIV viral load, education, sexual-activity, fertility desires, and economic independence are pertinent individual-level factors integral to the multi-level barriers to utilization of effective contraception among African WLHIV. National programs should prioritize strategies for effective integration of HIV and reproductive health care in the respective African countries.

Breastfeeding Among Women Living With HIV in the Era of Lifelong ART: An Observational Multicountry Study in Eastern and Southern Africa.

BACKGROUND: Lifelong antiretroviral treatment (ART) use is recommended for pregnant and breastfeeding (BF) women living with HIV (WLWH) to prevent perinatal HIV transmission and improve maternal health. We address 2 objectives in this analysis: (1) determine timing and factors associated with BF cessation and (2) assess the impact of BF on health of WLWH on ART. SETTING: This multicountry study included 8 sites in Uganda, Malawi, Zimbabwe, and South Africa. METHODS: This was a prospective study of WLWH on lifelong ART. These women initially participated from 2011 to 2016 in a randomized clinical trial (PROMISE) to prevent perinatal HIV transmission and subsequently reenrolled in an observational study (PROMOTE, 2016-2021) to assess ART adherence, safety, and impact. RESULTS: The PROMOTE cohort included 1987 women on ART. Of them, 752 breastfed and were included in analyses of objective 1; all women were included in analyses of objective 2. The median time to BF cessation varied by country (11.2-19.7 months). Country of residence, age, and health status of women were significantly associated with time to BF cessation (compared with Zimbabwe: Malawi, adjusted hazard ratio [aHR] 0.50, 95% confidence interval [95% CI]: 0.40 to 0.62, P < 0.001; South Africa, aHR 1.49, 95% CI: 1.11 to 2.00, P = 0.008; and Uganda, aHR 1.77, 95% CI: 1.37 to 2.29, P < 0.001). Women who breastfed had lower risk of being "unwell" compared with women who never breastfed (adjusted rate ratio 0.87, 95% CI: 0.81 to 0.95 P = 0.030). CONCLUSION: Women on lifelong ART should be encouraged to continue BF with no concern for their health. Time to BF cessation should be monitored for proper counseling in each country.

Indirect serum biomarkers perform sub optimally in screening for significant liver fibrosis among HIV-infected and uninfected adults in Uganda.

Introduction: Indirect serum bio-markers present an acceptable noninvasive and cheap alternative for screening of significant liver fibrosis (SLF). Evaluation of their use in resource limited settings is important to determine their utility. Methods: We conducted a cross sectional study among 520 HIV infected and HIV uninfected adults attending care clinics in Kampala Uganda. Presence of SLF was determined using Fibroscan® liver stiffness measurement of ≥7.2KPa. The diagostic value of indirect serum bio-markers for diagnosis of SLF was evaluated using the area under the receiver operating characteristics curve (AUROC) using Fibroscan® as gold standard. Results: Overall AUROC values for Age Platelet Index (API), Aspartate to Alanine Ratio (AAR), AST-to-Platelet Ratio Index (APRI), Fibrosis Index based on 4 Factors (FIB-4) and Gamma glutamyl transferase to Platelet Ratio Index (GPR) were 0.52, 0.49, 0.55, 0.55 and 0.54 respectively. Among HIV-infected participants AUROC values were slightly improved at predicting presence of SLF but still under 70%. Conclusion: Despite APRI and FIB-4 being more likely to identify participants with SLF, the overall diagnostic value of all serum bio-markers was poor with and without stratification by HIV status. We recommend the use of Fibroscan® technology as more accurate non-invasive diagnostic method for screening of SLF.

Effects of long-term antiretroviral therapy in reproductive-age women in sub-Saharan Africa (the PEPFAR PROMOTE study): a multi-country observational cohort study.

BACKGROUND: We report the long-term impact of ART in women of reproductive age (15-49 years) in Africa who have been using ART for up to 10 years. We assess outcomes of retention, adherence, maternal health, fertility intentions, and safety. METHODS: This longitudinal, multicountry study (PROMOTE) enrolled women who initiated ART in an earlier perinatal clinical trial, PROMISE. PROMISE occurred from 2011 to 2016 and PROMOTE follow-up started in 2016 and is ongoing. The PROMOTE study was done at eight sites in four countries: Malawi (Blantyre and Lilongwe), South Africa (Durban and Soweto), Uganda (Kampala), and Zimbabwe (Harare, Seke North, and St Mary's). After baseline enrolment, women and their children are followed up every 6 months to collect information on medical history, antiretroviral therapy (ART) use, adherence, and health information, and to do physical examinations and laboratory tests. Obesity was defined as a body-mass index of 30 kg/m2 or more. Data analyses were restricted to summaries of the main long-term outcomes (retention, adherence, maternal health, fertility intentions, and safety). We used descriptive and stratified analyses, and estimated rates using person-years of follow-up and computed probabilities based on Kaplan-Meier methods. FINDINGS: PROMOTE enrolled 1987 mothers and 2522 children. The median follow-up time for mothers was 41·8 (IQR 35·8-42·0) months and for children was 35·7 (23·8-42·0) months. Overall retention rates were 96·5% for mothers and 94·3% for children at 12 months, and, at 42 months, were 88·9% for mothers and 85·4% for children. 1115 (89·1%) of 1252 women had an undetectable viral load at 42 months, which varied by site (81·7-93·8%). Reported maternal health improved over time, with the proportion of women with excellent to very good health increasing from 67·5% at baseline to 87·5% at 42 months, the proportion of unwell participants who visited a health centre declining from 14·7% to 2·8%, and the proportion of those admitted to hospital declining from 1·5% to 1·0%. The desire to have more children was consistently high at some sites. The proportion of women with obesity was high in South Africa and increased over time from 40·2% at baseline to 52·8% at 42 months. The overall pregnancy rate was 17·6 (95% CI 16·5-18·7) per 100 women-years, and mortality rates were 2·4 (1·4-3·9) per 1000 person-years for mothers and 3·4 (2·2-5·10) per 1000 person-years for children (0-9 years). INTERPRETATION: The findings from this multicountry study are reassuring. These findings show that African women can consistently use ART for a long period after initiation, and long-term benefits can be maintained. Services to support maternal HIV care, treatment, and reproductive health should be strengthened. FUNDING: US President's Emergency Plan for AIDS Relief.

Growth deficits in antiretroviral and HIV-exposed uninfected versus unexposed children in Malawi and Uganda persist through 60 months of age.

OBJECTIVE: To compare childhood physical growth among antiretroviral drug and maternal HIV-exposed uninfected (AHEU) compared with HIV-unexposed uninfected (HUU) children. DESIGN: Longitudinal follow-up of PROMISE trial (NCT01061151) AHEU and age-matched and sex-matched HUU children, enrolled (September 2013 to October 2014) in Malawi and Uganda. METHOD: We compared WHO population standardized z-scores [height-for-age (HAZ), weight-for-age (WAZ), weight-for-height (WHZ), head-circumference-for-age (HCAZ) at 12, 24, 36, 48, and 60 months of age]. We evaluated HUU versus AHEU [in-utero combination antiretroviral treatment (cART) versus Zidovudine (ZDV) alone]; stratified by country, using longitudinal linear and generalized linear mixed models. RESULTS: Of 466 Malawian and 477 Ugandan children, median maternal age at enrollment was 24.5 years (Malawi) and 27.8 years (Uganda); more than 90% were breastfed through 12 months except Uganda AHEU (64.0%). HAZ scores (adjusted for maternal age, breastfed, and socioeconomic status) were lower among AHEU versus HUU children at every time point, significant (P < 0.05) among Ugandan but not Malawian children. Similar patterns were seen for WAZ but not for WHZ or HCAZ scores. High stunting was observed in both countries, significantly higher in Malawi; and higher among AHEU versus HUU children through 48 months of age, significantly (P < 0.05) among Ugandan but not Malawian children. We found no differences in childhood growth trajectories with in-utero exposures to ZDV compared with cART. CONCLUSION: AHEU versus HUU children had lower median LAZ and WAZ scores persisting through 60 months of age. However, proportions of children with stunting or underweight decreased after 24 months of age.

Neurodevelopmental outcomes of HIV/antiretroviral drug perinatally exposed uninfected children aged 3-6 years.

OBJECTIVE: Given the roll out of maternal antiretroviral therapy (ART) for prevention-of-perinatal-HIV-transmission, increasing numbers of children are perinatally HIV/antiretroviral exposed but uninfected (CAHEU). Some studies suggest CAHEU may be at increased risk for neurodevelopmental (ND) deficits. We aimed to assess ND performance among preschool CAHEU. DESIGN: This cross-sectional study assessed ND outcomes among 3-6-year-old CAHEU at entry into a multicountry cohort study. METHODS: We used the Mullen Scales of Early Learning (MSEL) and Kaufman Assessment Battery for Children (KABC-II) to assess ND status among 3-6-year-old CAHEU at entry into the PROMISE Ongoing Treatment Evaluation (PROMOTE) study conducted in Uganda, Malawi, Zimbabwe and South Africa. Statistical analyses (Stata 16.1) was used to generate group means for ND composite scores and subscale scores, compared to standardized test score means. We used multivariable analysis to adjust for known developmental risk factors including maternal clinical/socioeconomic variables, child sex, growth-for-age measurements, and country. RESULTS: 1647 children aged 3-6 years had baseline ND testing in PROMOTE; group-mean unadjusted Cognitive Composite scores on the MSEL were 85.8 (standard deviation [SD]: 18.2) and KABC-II were 79.5 (SD: 13.2). Composite score group-mean differences were noted by country, with South African and Zimbabwean children having higher scores. In KABC-II multivariable analyses, maternal age >40 years, lower education, male sex, and stunting were associated with lower composite scores. CONCLUSIONS: Among a large cohort of 3-6 year old CAHEU from eastern/southern Africa, group-mean composite ND scores averaged within the low-normal range; with differences noted by country, maternal clinical and socioeconomic factors.

Impact of Motivational Enhanced Adherence Counseling and Point-of-Care Viral Load Monitoring on Viral Load Outcome in Women on Life-Long ART: A Randomized Pilot Study.

We piloted the combined effectiveness of point-of-care viral load monitoring plus motivational enhanced adherence counseling (intervention) compared with routine care (control) in women identified at risk of virologic failure in the PROMOTE study in Zimbabwe. In an unblinded randomized study, consenting women with last viral load ≥200 copies/ml and/or pill count outside 90-110% range were randomized 1 : 1 to receive the intervention or continue routine care, comprising laboratory-based VL monitoring and standard EAC, from trained nurses and counsellors. Viral load was measured 0, 3, 6, and 12 months after enrolment. We compared viral suppression <200 copies/ml at 6 and 12 months between the arms through Fisher's exact test and sought associated factors by logistic regression with a 95% confidence interval (CI). Between December 2018 and July 2019, 50 women were enrolled (25 intervention and 25 controls) and followed until November 2020. At entry, 60% of the women were virally suppressed, 52% intervention vs. 68% control arm. Viral suppression was balanced between the two arms (p value = 0.248). At month 6 post study entry (primary endpont), 64% of the women retained in care were virally suppressed, 54% intervention vs. 76% control arm (p value = 0.124). At month12 post study entry (secondary endpoint), 69% of the women retained in care were virally suppressed, 67% intervention vs. 71% control arm women (p value = 0.739). More intervention women completed all scheduled sessions by month 6. Control group women were more likely to be virally suppressed at both timepoints. Only 25% had treatment switch by 12 months. Despite intense adherence support and viral load monitoring, sustained viral suppression remained elusive in women identified at risk of viral failure. These findings highlight the continued need for effective adherence intervention for women with unsuppressed HIV viral loads, efficient treatment switch strategies, as well as drug level monitoring.

Mentorship needs at academic institutions in resource-limited settings: a survey at Makerere University College of Health Sciences.

BACKGROUND: Mentoring is a core component of medical education and career success. There is increasing global emphasis on mentorship of young scientists in order to train and develop the next leaders in global health. However, mentoring efforts are challenged by the high clinical, research and administrative demands. We evaluated the status and nature of mentoring practices at Makerere University College of Health Sciences (MAKCHS). METHODS: Pre-tested, self-administered questionnaires were sent by email to all Fogarty alumni at the MAKCHS (mentors) and each of them was requested to complete and email back the questionnaire. In addition to training level and number of mentors, the questionnaires had open-ended questions covering themes such as; status of mentorship, challenges faced by mentors and strategies to improve and sustain mentorship within MAKCHS. Similarly, open-ended questionnaires were sent and received by email from all graduate students (mentees) registered with the Uganda Society for Health Scientists (USHS). Qualitative data from mentors and mentees was analyzed manually according to the pre-determined themes. RESULTS: Twenty- two out of 100 mentors responded (14 email and 8 hard copy responses). Up to 77% (17/22) of mentors had Master's-level training and only 18% (4/22) had doctorate-level training. About 40% of the mentors had ≥ two mentees while 27% had none. Qualitative results showed that mentors needed support in terms of training in mentoring skills and logistical/financial support to carry out successful mentorship. Junior scientists and students reported that mentorship is not yet institutionalized and it is currently occurring in an adhoc manner. There was lack of awareness of roles of mentors and mentees. The mentors mentioned the limited number of practicing mentors at the college and thus the need for training courses and guidelines for faculty members in regard to mentorship at academic institutions. CONCLUSIONS: Both mentors and mentees were willing to improve mentorship practices at MAKCHS. There is need for institutional commitment to uphold and sustain the mentorship best practices. We recommend a collaborative approach by the stakeholders in global health promotion to build local capacity in mentoring African health professionals.

Corrigendum to "Hepatitis B birth dose vaccination for newborns in Uganda: A qualitative inquiry on pregnant women's perceptions, barriers and preferences" [J Virus Eradic 7(2) (2021) 100039].

[This corrects the article DOI: 10.1016/j.jve.2021.100039.].

Hepatitis B birth dose vaccination for newborns in Uganda: A qualitative inquiry on pregnant women's perceptions, barriers and preferences.

BACKGROUND: Sub-Saharan Africa continues with very low hepatitis B (HBV) birth dose vaccination coverage. To guide policy on HBV vaccine for newborns, we explored perceptions, barriers and preferences of pregnant women regarding HBV and the HBV birth dose vaccination. METHODS: We conducted eight focus groups discussions (FGDs) among 70 pregnant women, stratified by rural-urban residence, age and education level, using a structured focus group discussion guide to explore birth dose awareness, perceptions, barriers and preferences. Data were transcribed, coded and analysed using framework analysis. RESULTS: Perceptions related to HBV and liver cancer causes and prevention were diverse; most FGD participants did not perceive illnesses as distinctly different. Older women-groups, both urban and rural, had never heard about HBV, but were aware of liver cancer, viewing the disease as fatal. No FGD participants were aware of HBV birth dose. Concerns included vaccine safety, its availability to women who deliver outside the health system and mistrust in health-care worker (HCWs) when handling newborns. Rural-dwelling groups perceived absence of HBV services, while FGDs with young participants believed vaccine side-effects hampered birth dose planning. Most women-groups preferred (i) oral to injectable vaccines; (ii) receiving birth dose education during antenatal, to media-based education; (iii) that newborns receive the birth dose immediately after delivery in the mother's presence. CONCLUSION: Although the birth dose is acceptable among pregnant women, planners need to continuously engage them as key stakeholders during planning to address concerns, in order to raise confidence, maximize uptake and strengthen HBV eradication efforts.

Effect on growth of exposure to maternal antiretroviral therapy in breastmilk versus extended infant nevirapine prophylaxis among HIV-exposed perinatally uninfected infants in the PROMISE randomized trial.

BACKGROUND: Malnutrition is highly prevalent in HIV-exposed perinatally uninfected infants (HEUs) increasing the risk of morbidity and mortality throughout the life course. We set out to compare the effect of postnatal exposure to maternal antiretroviral therapy (mART) in breastmilk versus infant Nevirapine prophylaxis (iNVP) on somatic growth of HEUs in the randomized PROMISE trial. METHODS AND FINDINGS: We randomized 2431 mothers with HIV and their 2444 HEUs from six African countries and India 6-14 days after delivery to mART or iNVP for prevention of breastmilk HIV transmission. The mART regimen contained tenofovir/emtricitabine (99%) plus lopinavir/ritonavir. Infant growth parameters were compared at postnatal week 10, 26, 74 and 104 using World Health Organization (WHO) z-scores for length-for-age (LAZ), weight-for-age (WAZ), and head circumference-for-age (HCAZ). Week 26 LAZ was the primary endpoint measure. Student T-tests compared mean LAZ, WAZ, and HCAZ; estimated mean and 95% confidence interval (CI) are presented. Maternal and infant baseline characteristics were comparable between study arms. The estimated median breastfeeding duration was 70 weeks. After a mean follow-up of 88 weeks, mean LAZ and WAZ were below the WHO reference population mean at all timepoints, whereas mean HCAZ was not. The mART and iNVP arms did not differ for the primary outcome measure of LAZ at week 26 (p-value = 0.39; estimated mean difference (95%CI) of -0.05 (-0.18, 0.07)) or any of the other secondary growth outcome measures or timepoints (all p-values≥0.16). Secondary analyses of the primary outcome measure adjusting for week 0 LAZ and other covariates did not change these results (all p-values≥0.09). However, infants assigned to mART were more likely to have stunting compared to iNVP infants at week 26 (odds ratio (95% CI): 1.28 (1.05, 1.57)). CONCLUSIONS: In HEUs, growth effects from postnatal exposure to mART compared to iNVP were comparable for measures on length, weight and head circumference with no clinically relevant differences between the groups. Despite breastfeeding into the second year of life, length and weight were below reference population means at all ages in both arms. Further investment is needed to optimize postnatal growth of infants born to women with HIV. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number NCT01061151.

Impact of postpartum tenofovir-based antiretroviral therapy on bone mineral density in breastfeeding women with HIV enrolled in a randomized clinical trial.

OBJECTIVES: We set out to evaluate the effect of postnatal exposure to tenofovir-containing antiretroviral therapy on bone mineral density among breastfeeding women living with HIV. DESIGN: IMPAACT P1084s is a sub-study of the PROMISE randomized trial conducted in four African countries (ClinicalTrials.gov number NCT01066858). METHODS: IMPAACT P1084s enrolled eligible mother-infant pairs previously randomised in the PROMISE trial at one week after delivery to receive either maternal antiretroviral therapy (Tenofovir disoproxil fumarate / Emtricitabine + Lopinavir/ritonavir-maternal TDF-ART) or administer infant nevirapine, with no maternal antiretroviral therapy, to prevent breastmilk HIV transmission. Maternal lumbar spine and hip bone mineral density were measured using dual-energy x-ray absorptiometry (DXA) at postpartum weeks 1 and 74. We studied the effect of the postpartum randomization on percent change in maternal bone mineral density in an intention-to-treat analysis with a t-test; mean and 95% confidence interval (95%CI) are presented. RESULTS: Among 398/400 women included in this analysis, baseline age, body-mass index, CD4 count, mean bone mineral density and alcohol use were comparable between study arms. On average, maternal lumbar spine bone mineral density declined significantly through week 74 in the maternal TDF-ART compared to the infant nevirapine arm; mean difference (95%CI) -2.86 (-4.03, -1.70) percentage points (p-value <0.001). Similarly, maternal hip bone mineral density declined significantly more through week 74 in the maternal TDF-ART compared to the infant nevirapine arm; mean difference -2.29% (-3.20, -1.39) (p-value <0.001). Adjusting for covariates did not change the treatment effect. CONCLUSIONS: Bone mineral density decline through week 74 postpartum was greater among breastfeeding HIV-infected women randomized to receive maternal TDF-ART during breastfeeding compared to those mothers whose infants received nevirapine prophylaxis.

Prevalence and Factors Associated With Liver Fibrosis Among Adult HIV-Infected Patients Attending Urban and Rural Care Clinics in Uganda.

BACKGROUND: Liver fibrosis is common among HIV-infected patients. Risk factors vary by location. Understanding this variation may inform prevention strategies. We compared the prevalence and correlates of liver fibrosis among HIV-infected patients attending care clinics in Uganda. METHODS: This was a cross-sectional study involving 2030 HIV-infected patients attending care clinics in urban and rural Uganda. Liver fibrosis was defined as liver stiffness measurement (LSM) >7.1 KPa. Proportions and correlates of liver fibrosis were assessed and compared using logistic regression stratified by gender and site. RESULTS: Prevalence of liver fibrosis was higher among participants in the rural clinic (15% vs 11%; P = .017). History of tobacco use (urban P = .022; rural P = .035) and serologic evidence of hepatitis C infection (HCV; urban P = .028; rural P = .03) was associated with liver fibrosis in all men. Elevated liver transaminases (urban P = .002; rural P = .028) and increasing age (urban P = .008; rural P = .052) were risk factors among all women. Tobacco use among women was only a risk factor in those attending the rural clinic (P = .003), and detectable HIV viral load (P = .002) for men in the urban clinic. CONCLUSIONS: Liver fibrosis is prevalent among HIV-infected persons in Uganda. HIV viral suppression and avoiding tobacco may be strategies to prevent liver fibrosis and cancer risk.

Decreased growth among antiretroviral drug and HIV-exposed uninfected versus unexposed children in Malawi and Uganda.

OBJECTIVE: To compare growth among antiretroviral drug and maternal HIV-exposed uninfected (AHEU) versus age-matched and sex-matched HIV-unexposed uninfected (HUU) children. DESIGN: Prospective cohort of AHEU children identified from the PROMISE trial (NCT01061151: clinicaltrials.gov registry) and age-matched and sex-matched HUU controls from child-wellness clinics, enrolled (September 2013 to October 2014) in Malawi and Uganda. METHODS: Weight-for-age (WAZ), length-for-age (LAZ), weight-for-length (WLZ), and head-circumference-for-age (HCAZ) z-scores were derived at 12 months and 24 months of age. Wilcoxon Rank-Sum and Fisher's exact tests were used for unadjusted exposure group comparisons. Generalized Estimating Equations models estimated adjusted relative risks (aRR) for poor growth outcomes. RESULTS: Overall, 471 (50.5%) AHEU and 462 (49.5%) HUU children were assessed. Ugandan AHEU compared with HUU children had significantly lower mean LAZ (P < 0.001) and WAZ (P < 0.001) at 12 and 24 months of age and HCAZ (P = 0.016) at 24 months, with similar but not significant differences among Malawian AHEU and HUU children. The risk of stunting (more than two standard deviations below the WHO population LAZ median) was increased among AHEU versus HUU children: aRR = 2.13 (95% confidence interval (CI): 1.36-3.33), P = 0.001 at 12 months, and aRR = 1.67 (95% CI 1.16-2.41), P = 0.006 at 24 months of age in Uganda; and aRR = 1.32 (95% CI 1.10-1.66), P = 0.018, at 24 months of age in Malawi. The risk of HCAZ below WHO median was increased among AHEU versus HUU children at 24 months of age, aRR = 1.35 (95% CI 1.02-1.79), P = 0.038 in Uganda; and aRR = 1.35 (95% CI 0.91-2.02), P = 0.139 in Malawi. CONCLUSION: Perinatal exposures to maternal HIV and antiretroviral drugs were associated with lower LAZ (including stunting), WAZ and HCAZ at 24 months of age compared with HUU children.

Antenatal Intracellular Concentrations of Tenofovir Diphosphate and Emtricitabine Triphosphate and Associations Between Tenofovir Diphosphate and Severe Adverse Pregnancy Outcomes: IMPAACT-PROMISE (1077BF) Trial.

BACKGROUND: In the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial, tenofovir disoproxil fumarate (TDF) use was associated with moderate or severe adverse pregnancy/neonatal outcomes. This study characterized tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations in dried blood spots (DBS) and assessed association between severe adverse pregnancy/neonatal outcomes and TFV-DP concentration. METHODS: Retrospective case-control study of PROMISE trial arm-C women randomized to receive TDF, FTC, and ritonavir-boosted lopinavir (LPV/r), who took at least 1 dose of TDF + FTC and had week-4 postrandomization DBS drawn before delivery. Cases, defined as severe adverse pregnancy/neonatal outcomes (very preterm delivery before 34 weeks of gestation, stillbirth ≥20 weeks of gestation, or infant death before 14 days-of-age), were matched to controls (1:2 ratio) by site and gestational age at entry. Week 4 and week 8 DBS samples were assayed for TFV-DP and FTC-TP by liquid chromatography and tandem mass spectrometry. Associations were tested using Wilcoxon rank test and conditional logistic regression. RESULTS: Of 447 PROMISE arm-C women, 33 met case definitions, and overall, 22 cases and 44 controls were analyzed. Median (interquartile range) concentrations of TFV-DP at weeks 4 and 8 were 706 (375-1023) fmol/punch and 806 (414-1265) fmol/punch, respectively. Odds ratio (95% confidence interval) for severe adverse pregnancy/neonatal outcome with natural log of TFV-DP concentrations as the predictor were 1.27 (0.74 to 2.18) and 1.74 (0.66 to 4.60) at weeks 4 and 8, respectively. Median (interquartile range) concentrations of FTC-TP at weeks 4 and 8 were 0.27 (0.05-0.36) pmol/punch and 0.29 (0.05-0.40) pmol/punch, respectively. CONCLUSIONS: TFV-DP concentrations in DBS appeared not to be associated with severe adverse pregnancy/neonatal outcomes, although sample size was limited.

Factors associated with unsuppressed viremia in women living with HIV on lifelong ART in the multi-country US-PEPFAR PROMOTE study: A cross-sectional analysis.

BACKGROUND: Despite recent efforts to scale-up lifelong combination antiretroviral therapy (cART) in sub-Saharan Africa, high rates of unsuppressed viremia persist among cART users, and many countries in the region fall short of the UNAIDS 2020 target to have 90% virally suppressed. We sought to determine the factors associated with unsuppressed viremia (defined for the purpose of this study as >200 copies/ml) among sub-Saharan African women on lifelong cART. METHODS: This cross-sectional analysis was based on baseline data of the PROMOTE longitudinal cohort study at 8 sites in Uganda, Malawi, Zimbabwe and South Africa. The study enrolled 1987 women living with HIV who initiated lifelong cART at least 1-5 years ago. Socio-demographic, clinical, and cART adherence data were collected. We used multivariable Poisson regression with robust variance to identify factors associated with unsuppressed viremia. RESULTS: At enrolment, 1947/1987 (98%) women reported taking cART. Of these, HIV-1 remained detectable in 293/1934 (15%), while 216/1934 (11.2%) were considered unsuppressed (>200 copies/ml). The following factors were associated with an increased risk of unsuppressed viremia: not having household electricity (adjusted prevalence risk ratio (aPRR) 1.74, 95% confidence interval (CI) 1.28-2.36, p<0.001); not being married (aPRR 1.32, 95% CI 0.99-1.78, p = 0.061), self-reported missed cART doses (aPRR 1.63, 95% CI 1.24-2.13, p<0.001); recent hospitalization (aPRR 2.48, 95% CI 1.28-4.80, p = 0.007) and experiencing abnormal vaginal discharge in the last three months (aPRR 1.88; 95% CI 1.16-3.04, p = 0.010). Longer time on cART (aPRR 0.75, 95% CI 0.64-0.88, p<0.001) and being older (aPRR 0.77, 95% CI 0.76-0.88, p<0.001) were associated with reduced risk of unsuppressed viremia. CONCLUSION: Socioeconomic barriers such as poverty, and individual barriers like not being married, young age, and self-reported missed doses are key predictors of unsuppressed viremia. Targeted interventions are needed to improve cART adherence among women living with HIV with this risk factor profile.