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Women living with HIV and breast cancer have poorer survival than HIV-negative women. Efavirenz-estrogen interactions are documented; however, the survival impact is unknown. Survival between women with estrogen-receptor positive breast cancer taking efavirenz (n = 38) and nonefavirenz regimens (n = 51) were compared. The 5-year overall-survival was 48.9% [95% confidence interval (CI) 33.0-72.2 and 51.1% (95% CI 34.0-76.8)] in the efavirenz and nonefavirenz groups, respectively suggesting efavirenz is unlikely driving poorer survival in women living with HIV and estrogen-receptor positive breast cancer., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: We sought to determine hepatitis B surface antigen (HBsAg) loss and its predictors among people with chronic hepatitis B (CHB) infections and HIV (PWH) in Botswana., Methods: Archived plasma samples from a cohort of PWH in Botswana (2013-2018) with 3 yearly time-points were used. Samples were screened for HBsAg, immunoglobulin M HBV core antibodies (anti-HBc IgM) and HBV e-antigen (HBeAg) at all time points. HBV deoxyribonucleic acid (DNA) quantification was done at baseline. The Wilcoxon rank-sum was used to compare continuous variables while the chi-squared test and Fishers exact test were used for categorical data wherever appropriate. Logistic regression was used to assess predictors of seroclearance., Results: Of 141 participants with HBsAg-positive serology (HBsAg+) at baseline, 92.2% (131/141) [95% confidence interval (CI) 87.4-96.1] were persistently HBsAg+ at year 1. We report a HBsAg loss of 7.1% (10/141) (95% CI 3.9-12.6) among participants with negative HBeAg and negative IgM serologies. HBsAg loss was 6.3% (7/111) among antiretroviral therapy (ART)-experienced participants and 10.7% (3/28) (95% CI 0.4-5.0) in ART-naive participants. Most participants who had positive anti-HBc IgM serology and did not lose HBsAg were on either lamivudine (3TC)-based therapy or non-tenofovir disoproxil fumarate (TDF)-based therapy, except for one participant. The participants also had varying HBeAg status. HBsAg loss was independent of HIV viral load, CD4 + cell count, age, and sex., Conclusion: We report a HBsAg loss of 6.3% over a 3-year period among ART-experienced CHB participants. Future studies that focus on HBsAg loss in mono-infected patients and the possible correlation between HBeAg status and HBsAg loss are warranted., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Randomized trials in pregnancy are extremely challenging, and observational studies are often the only option to evaluate medication safety during pregnancy. However, such studies are often susceptible to immortal time bias if treatment initiation occurs after time zero of follow-up. We describe how emulating a sequence of target trials avoids immortal time bias and apply the approach to estimate the safety of antibiotic initiation between 24 and 37 weeks gestation on preterm delivery., Methods: The Tsepamo Study captured birth outcomes at hospitals throughout Botswana from 2014 to 2021. We emulated 13 sequential target trials of antibiotic initiation versus no initiation among individuals presenting to care <24 weeks, one for each week from 24 to 37 weeks. For each trial, eligible individuals had not previously initiated antibiotics. We also conducted an analysis susceptible to immortal time bias by defining time zero as 24 weeks and exposure as antibiotic initiation between 24 and 37 weeks. We calculated adjusted risk ratios (RR) and 95% confidence intervals (CI) for preterm delivery., Results: Of 111,403 eligible individuals, 17,009 (15.3%) initiated antibiotics between 24 and 37 weeks. In the sequence of target trials, RRs (95% CIs) ranged from 1.04 (0.90, 1.19) to 1.24 (1.11, 1.39) (pooled RR: 1.11 [1.06, 1.15]). In the analysis susceptible to immortal time bias, the RR was 0.90 (0.86, 0.94)., Conclusions: Defining exposure as antibiotic initiation at any time during follow-up after time zero resulted in substantial immortal time bias, making antibiotics appear protective against preterm delivery. Conducting a sequence of target trials can avoid immortal time bias in pregnancy studies., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To evaluate the combined association of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human immunodeficiency virus (HIV) infection on adverse birth outcomes in an HIV-endemic region., Methods: The Tsepamo Study abstracts data from antenatal and obstetric records in government maternity wards across Botswana. We assessed maternal mortality and adverse birth outcomes for all singleton pregnancies from September 2020 to mid-November 2021 at 13 Tsepamo sites among individuals with documented SARS-CoV-2 screening tests and known HIV status., Results: Of 20,410 individuals who gave birth, 11,483 (56.3%) were screened for SARS-CoV-2 infection; 4.7% tested positive. People living with HIV were more likely to test positive (144/2,421, 5.9%) than those without HIV (392/9,030, 4.3%) (P=.001). Maternal deaths occurred in 3.7% of those who had a positive SARS-CoV-2 test result compared with 0.1% of those who tested negative (adjusted relative risk [aRR] 31.6, 95% CI 15.4-64.7). Maternal mortality did not differ by HIV status. The offspring of individuals with SARS-CoV-2 infection experienced more overall adverse birth outcomes (34.5% vs 26.6%; aRR 1.2, 95% CI 1.1-1.4), severe adverse birth outcomes (13.6% vs 9.8%; aRR 1.2, 95% CI 1.0-1.5), preterm delivery (21.4% vs 13.4%; aRR 1.4, 95% CI 1.2-1.7), and stillbirth (5.6% vs 2.7%; aRR 1.7 95% CI 1.2-2.5). Neonates exposed to SARS-CoV-2 and HIV infection had the highest prevalence of adverse birth outcomes (43.1% vs 22.6%; aRR 1.7, 95% CI 1.4-2.0)., Conclusion: Infection with SARS-CoV-2 at the time of delivery was associated with 3.7% maternal mortality and 5.6% stillbirth in Botswana. Most adverse birth outcomes were worse among neonates exposed to both SARS-CoV-2 and HIV infection., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2022 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Individuals living with human immunodeficiency virus (HIV) who experience virological failure (VF) after combination antiretroviral therapy (cART) initiation may have had low-frequency drug resistance mutations (DRMs) at cART initiation. There are no data on low-frequency DRMs among cART-naïve HIV-positive individuals in Botswana., Methods: We evaluated the prevalence of low-frequency DRMs among cART-naïve individuals previously sequenced using Sanger sequencing. The generated pol amplicons were sequenced by next-generation sequencing., Results: We observed low-frequency DRMs (detected at <20% in 33/103 (32%) of the successfully sequenced individuals, of whom four also had mutations detected at >20%. K65R was the most common low-frequency DRM detected in 8 individuals. Eighty-two of the 103 individuals had follow-up viral load data while on cART. Twenty-seven of the 82 individuals harbored low-frequency DRMs. Only 12 of 82 individuals experienced VF. The following low-frequency DRMs were observed in four individuals experiencing VF: K65R, K103N, V108I, and Y188C. No statistically significant difference was observed in the prevalence of low-frequency DRMs between individuals experiencing VF (4/12) and those not experiencing VF (23/70) (P = .97). However, individuals with non-nucleoside reverse transcriptase inhibitors-associated low-frequency DRMs were 2.68 times more likely to experience VF (odds ratio, 2.68; 95% confidential interval, 0.4-13.9) compared with those without (P = .22)., Conclusion: Next-generation sequencing was able to detect low-frequency DRMs in this cohort in Botswana, but these DRMs did not contribute significantly to VF., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Investigation of the diagnostic yield of urine-based tuberculosis (TB) screening in patients with advanced HIV disease., Design: A cross-sectional screening study., Setting: HIV outpatient clinics and wards at two hospitals in Johannesburg, South Africa, between June 2015 and October 2017., Participants: Two hundred and one patients living with advanced HIV disease (CD4+ T-lymphocytes <100 cells/μl) attending healthcare facilities following cryptococcal antigen (CrAg) screening., Intervention: Screening for TB using sputum for microscopy, culture, and Xpert MTB/Rif and urine for lipoarabinomannan (LAM) and Xpert Ultra., Main Outcome Measures: Proportion of positive results using each testing modality, sensitivity, and specificity of urine-based testing compared with culture, and survival outcomes during 6 months follow up., Results: Urine was obtained from 177 of 181 (98%) participants and sputum from 91 (50%). Urine-based screening increased same-day diagnostic yield from 7 (4%) to 31 (17%). A positive urine test with either LAM or Xpert Ultra had 100% sensitivity (95% confidence interval, 59-100%) for detecting culture-positive TB at any site. Patients with newly diagnosed TB on urine-based screening were initiated on treatment and did not have excess mortality compared with the remainder of the cohort., Conclusion: Urine is an easily obtainable sample with utility for detecting TB in patients with advanced HIV disease. Combining urine and sputum-based screening in this population facilitates additional same-day TB diagnoses and early treatment initiation, potentially reducing the risk of TB-related mortality. Urine-based as well as sputum-based screening for TB should be integrated with CrAg screening in patients living with advanced HIV disease., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: We sought to determine vaccine antibody titres and the prevalence of hepatitis B surface antigen (HBsAg) in both HIV-positive and HIV-negative infants born to HIV-positive mothers in Botswana., Design: This was a retrospective cross-sectional study using 449 archived dried blood spot samples from both HIV-positive and HIV-negative infants collected between 2016 and 2018., Methods: We screened dried blood spot samples for HBsAg and determined hepatitis B surface antibody titres. We determined hepatitis B virus (HBV) genotypes by amplifying 415 base-pairs of the surface region., Results: HIV-positive infants mounted a significantly lower immune response to the HBV vaccine (P  < 0.001). Furthermore, a lower proportion of HIV-positive infants had protective hepatitis B surface antibody titres (74.5%) than HIV-negative infants (89.2%) (P < 0.001). HIV-positive infants were older and 50.9% of them had completed vaccination (P = 0.018). Of the 449 infant samples tested, three (0.67%) were positive for HBsAg. Of the three HBsAg-positive infants, two had protective titres (>10 mIU/ml). Two of the three HBV-positive infants were infected with genotype D3 and had no drug-resistance or escape mutations., Conclusion: Vaccine response was lower among HIV-positive infants compared with HIV-negative infants. HBV infections were observed in both HIV-positive and HIV-negative infants in Botswana. Studies to investigate additional preventive strategies to reduce HBV mother-to-child transmission are recommended., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: The two non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz (EFV) and nevirapine (NVP), are currently the core antiretroviral drugs for treatment of HIV in sub-Saharan Africa including Botswana. The drugs are metabolized by Cytochrome P450 2B6 (CYP2B6) liver enzyme. The CYP2B6 gene that encodes for metabolism of these drugs is known to be highly polymorphic. One of the polymorphism in the CYP2B6 gene, 516G>T, particularly the 516T allele, is known to confer poor metabolism of EFV and NVP. This may lead to high levels of plasma drug concentrations and development of treatment toxicities, like central nervous system toxicities, and cutaneous and hepatic toxicities, for EFV and NVP, respectively. The CYP2B6 516G allele on the other hand is associated with an extensive metabolism of the two NNRTIs drugs. We sought to establish association between possible developments of NNRTIs toxicities with CYP2B6 516G>T variation in Botswana.A total of 316 peripheral blood mononuclear cells samples were used in a retrospective view. All the samples were from participants on EFV/NVP-containing regimen with known toxicity output. TaqMan Real-Time PCR approach was applied for assessing CYP2B6 516 allele variation in cases with treatment toxicity and those without. Analysis was performed by chi-square statistics and logistic regression analysis.The rate of poor metabolizers among participants with toxicity and those without toxicity was 18.4% and 15.1%, respectively. The CYP2B6 516 genotype distribution comparisons between the participants with toxicity and those without were not statistically different (chi-square = .326; P = .568).CYP2B6 516 variation was not associated with NNRTI toxicity. No other factors were associated with toxicity when considering age, baseline body mass index, baseline CD4, baseline HIV viral load and adherence. The results were discussed in the context of all the studies done in Botswana to date., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Sexually transmitted infections (STIs) cause significant morbidity among women with HIV and increase HIV transmission. We estimated the prevalence of four STIs among women with HIV in sub-Saharan Africa (SSA) and compared prevalence among women with and without HIV., Design: Systematic review and meta-analysis., Methods: We searched for studies published 1 January 1999 to 19 December 2019 reporting prevalence of gonorrhea, chlamydia, trichomoniasis, or Mycoplasma genitalium among women with HIV in SSA. We excluded studies conducted in high-risk groups (e.g. female sex workers). We extracted data on laboratory-confirmed STIs among women with HIV, and when included, among women without HIV. We estimated pooled prevalence for each STI among women with HIV using inverse variance heterogeneity meta-analysis, compared prevalence to women without HIV, and examined the influences of region, clinical setting, and pregnancy status in subgroup analyses., Results: We identified 3756 unique records; 67 studies were included in the meta-analysis. Prevalence of gonorrhea, chlamydia, trichomoniasis, and M. genitalium was 3.5, 4, 15.6, and 10.2%, respectively. Chlamydia prevalence was lower in Eastern (2.8%) than in Southern (12.5%) and West/Central (19.1%) Africa combined. Prevalence of chlamydia and trichomoniasis was higher among pregnant (8.1%, 17.6%) than nonpregnant (1.7%, 12.3%) women. All STIs were more prevalent among women with than without HIV (relative risks ranging 1.54-1.89)., Conclusion: STIs are common among women with HIV in SSA, and more common among women with than without HIV. Integrated STI and HIV care could substantially impact STI burden among women with HIV, with potential downstream impacts on HIV transmission., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose of Review: Although cervical cancer is preventable, it is the leading cancer among women in southern Africa. The association of high-risk human papillomavirus (HR-HPV) with almost all invasive cervical cancers has led to the development of effective primary and secondary prevention measures. This review focuses on updated and new evidence of the epidemiology of HPV and HPV-based secondary prevention in southern Africa., Recent Findings: HR-HPV prevalence in southern Africa differs between regions, and varies most by HIV prevalence and age. HR-HPV prevalence among women living with HIV (WLWH) is reported between 29 and 59.7%, and between 16.2 and 25.2% among women without HIV. HPV16 is the most common HR-HPV type present in invasive cervical cancers in the region; and vaccination may potentially prevent approximately 80% of these cancers. Concerning preliminary data suggests faster development of new cervical precancer within a short follow-up period., Summary: We need tools that identify the small number of women with precancer from the many with transient HR-HPV infection in southern Africa. The high-volume of test-positive women leads to challenges in managing triage in a HR-HPV-based screening program. Longitudinal data from the entire region is urgently needed to guide effective implementation of HPV-based screening programs., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: In AIDS Clinical Trials Group study A5338, concomitant rifampicin, isoniazid, and efavirenz was associated with more rapid plasma medroxyprogesterone acetate (MPA) clearance compared to historical controls without tuberculosis or HIV therapy. We characterized the pharmacogenetics of this interaction., Methods: In A5338, women receiving efavirenz-based HIV therapy and rifampicin plus isoniazid for tuberculosis underwent pharmacokinetic evaluations over 12 weeks following a 150-mg intramuscular injection of depot MPA. Data were interpreted with nonlinear mixed-effects modelling. Associations between individual pharmacokinetic parameters and polymorphisms relevant to rifampicin, isoniazid, efavirenz, and MPA were assessed., Results: Of 62 A5338 participants in four African countries, 44 were evaluable for pharmacokinetic associations, with 17 CYP2B6 normal, 21 intermediate, and 6 poor metabolizers, and 5 NAT2 rapid, 20 intermediate, and 19 slow acetylators. There were no associations between either CYP2B6 or NAT2 genotype and MPA Cmin at week 12, apparent clearance, Cmax, area under the concentration-time curve (AUC) or half-life, or unexplained interindividual variability in clearance, and uptake rate constant or mean transit time of the slow-release fraction (P > 0.05 for each). In exploratory analyses, none of 28 polymorphisms in 14 genes were consistently associated with MPA pharmacokinetic parameters, and none withstood correction for multiple testing., Conclusions: Study A5338 suggested that more frequent depot MPA dosing may be appropriate for women receiving rifampicin, isoniazid, and efavirenz. The present results suggest that knowledge of CYP2B6 metabolizer or NAT2 acetylator status does not inform individualized DMPA dosing in this setting., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To describe the occurrence of HIV drug resistance mutations (DRMs) in both intact and defective HIV-1 cell-associated DNA (HIV-1 CAD) among early-treated infants., Design: The Botswana EIT Study (ClinicalTrials.gov NCT02369406) initiated antiretroviral therapy (ART) in the first week of life and evaluated HIV-1 in plasma and peripheral blood mononuclear cells (PBMCs)., Methodology: We analyzed 257 near-HIV-1 full-length sequences (nFLS) obtained by Illumina next-generation sequencing from infants near birth. Sanger sequencing of pol was performed for mothers at delivery and children with clinical failure through 96 weeks. DRMs were identified using the Stanford HIV Drug Resistance Database., Results: In 27 infants, median PBMC HIV-1 proviral load was 492 copies/ml [IQR: 78-1246 copies/ml] at a median of 2 days (range 1-32); 18 (66.7%) had no DRMs detected; six (22.2%) had DRMs detected in defective DNA only, and three (11.1%) had DRMs in both defective and intact DNA (P = 0.09). A total of 60 of 151 (37.7%) defective sequences had at least one DRM: 31.8% NNRTI, 15.2% NRTI, 5.3% protease inhibitor, and 15.5% INSTI-associated mutations. In intact sequences, 33 of 106 (31.1%) had at least 1 DRM: 29.2% NNRTI, 7.5% NRTI, 0.9% protease inhibitor, and no INSTI-associated mutations. For all three infants with intact sequence DRMs, corresponding DRMs occurred in maternal plasma at delivery. Archived DRMs were detectable at a later clinical rebound on only one occasion., Conclusion: Defective HIV-1 cell-associated DNA sequences may overestimate the prevalence of drug resistance among early-treated children. The impact of DRMs from intact proviruses on long-term treatment outcomes warrants further investigation., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective(s): To determine the proportion of individuals linking to HIV-care with advanced HIV-disease (CD4 cell counts ≤200 cells/μl) in the Botswana Combination Prevention Project, describe the characteristics of these individuals, and examine treatment outcomes., Design: A subanalysis of a cluster-randomized HIV-prevention trial. HIV status was assessed in 16-64-year-olds through home and mobile testing. All HIV-positive persons not on antiretroviral therapy were referred to local Ministry of Health and Wellness clinics for treatment., Methods: Analysis was restricted to the 15 intervention clusters. The proportion of individuals with advanced HIV disease was determined; associations between advanced HIV disease and sex and age explored; and rates of viral suppression determined at 1-year. Mortality and retention in care were compared between CD4 strata (CD4 cell counts ≤200 vs. >200 cells/μl)., Results: Overall, 17.2% [430/2499; 95% confidence interval (CI) 15.7-18.8%] of study participants had advanced HIV disease (CD4 cell counts ≤200 cells/μl) at time of clinic linkage. Men were significantly more likely to present with CD4 cell counts 200 cells/μl or less than women [23.7 vs. 13.4%, adjusted odds ratio 1.9, 95% CI 1.5-2.3]. The risk of advanced HIV disease increased with increasing age (adjusted odds ratio 2.2, 95% CI 1.4-3.2 >35 vs. <25 years). Patients with CD4 cell counts 200 cells/μl or less had significantly higher rates of attrition from care during follow-up (hazards ratio 1.47, 95% CI 1.1-2.1)., Conclusion: Advanced HIV disease due to late presentation to or disengagement from antiretroviral therapy care remains common in the Treat All era in Botswana, calling for innovative testing, linkage, and treatment strategies to engage and retain harder-to-reach populations in care.

To determine effects of cryptococcal meningitis (CM) on human immunodeficiency virus (HIV)-1C cerebrospinal fluid (CSF) viral escape, CSF/plasma viral discordance, and drug resistance mutation (DRM) discordance between CSF and plasma compartments, we compared CSF and plasma viral load (VL) and DRMs in individuals with HIV-associated CM in Botswana.This cross-sectional study utilized 45 paired CSF/plasma samples from participants in a CM treatment trial (2014-2016). HIV-1 VL was determined and HIV-1 protease and reverse transcriptase genotyping performed. DRMs were determined using the Stanford HIV database. CSF viral escape was defined as HIV-1 ribonucleic acid ≥0.5 log10 higher in CSF than plasma and VL discordance as CSF VL > plasma VL.HIV-1 VL was successfully measured in 39/45 pairs, with insufficient sample volume in 6; 34/39 (87.2%) participants had detectable HIV-1 in plasma and CSF, median 5.1 (interquartile range: 4.7-5.7) and 4.6 (interquartile range:3.7-4.9) log10 copies/mL, respectively (P≤.001). CSF viral escape was present in 1/34 (2.9%) and VL discordance in 6/34 (17.6%). Discordance was not associated with CD4 count, antiretroviral status, fungal burden, CSF lymphocyte percentage nor mental status. Twenty-six of 45 (57.8%) CSF/plasma pairs were successfully sequenced. HIV-1 DRM discordance was found in 3/26 (11.5%); 1 had I84IT and another had M46MI in CSF only. The third had K101E in plasma and V106 M in CSF.Our findings suggest that HIV-1 escape and DRM discordance may occur at lower rates in participants with advanced HIV-disease and CM compared to those with HIV associated neurocognitive impairment.

Background: Risk for nondiagnostic and false-positive HIV testing has not been quantified for neonates., Methods: From April 2015 to July 2018, we screened HIV-exposed infants in Botswana less than 96 h from birth by qualitative DNA PCR. Repeat blood draws for DNA and RNA PCR testing occurred for initial positive and indeterminate results to establish final diagnosis. We compared screening DNA PCR cycle threshold values with final HIV status of the child., Results: Of 10 622 HIV-exposed infants, 10 549 (99.3%) had no HIV DNA detected (negative), 42 (0.4%) had HIV DNA detected (positive), and 31 (0.3%) tested indeterminate at first HIV screen. Repeat testing identified 2 (5.0%) of 40 positive screens (2 declined additional testing) as false positives and confirmed 2 (6.5%) of 31 indeterminate screens as infected. Median cycle threshold value at screening was 28.1 (IQR 19.8--34.8) for children with final positive status, and 35.5 (IQR 32.8--41.4) for indeterminates who were ultimately negative. Six (15%) of 40 infants with final positive status had cycle threshold value greater than 33 at first screen, whereas 3 (9.7%) of 31 indeterminates with final negative status had cycle threshold value 33 or less at first screen. This threshold resulted in a negative predictive value of 82% and a positive predictive value of 92% for a single screen., Conclusion: Although a DNA PCR cycle threshold value of 33 was predictive of the final HIV status in newborns, overlap occurred for true positives, false positives, and initial indeterminates. Testing additional samples should be standard practice for positive and indeterminate HIV DNA PCR tests in the first week of life.

Background: Intensified viral load monitoring for pregnant and breastfeeding women has been proposed to help address concerns around antiretroviral therapy (ART) adherence, viraemia and transmission risk, but there have been no systematic evaluations of existing policies., Methods: We used an individual Monte Carlo simulation to describe longitudinal ART adherence and viral load from conception until 2 years' postpartum. We applied national and international guidelines for viral load monitoring to the simulated data. We compared guidelines on the percentage of women receiving viral load monitoring and the percentage of women monitored at the time of elevated viral load., Results: Coverage of viral load monitoring in pregnancy and breastfeeding varied markedly, with between 14% and 100% of women monitored antenatally and 38-98% monitored during breastfeeding. Specific recommendations for testing at either a fixed gestation or a short, fixed period after ART initiation achieved more than 95% testing in pregnancy but this was much lower (14-83%) among guidelines with no special stipulations. By the end of breastfeeding, only a small proportion of simulated episodes of elevated viral load more than 1000 copies/ml were successfully detected by monitoring (range, 20-50%)., Discussion: Although further research is needed to understand optimal viral load frequency and timing in this population, these results suggest that current policies yield suboptimal detection of elevated viral load in pregnant and breastfeeding women.

Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection is highest in sub-Saharan Africa and results in accelerated clinical outcomes compared with HBV or HIV mono-infection. HBV clearance rates are higher in healthy adults; however, in sub-Saharan Africa, there are limited data on clearance of incident HBV in HIV-infected adults. Therefore, we sought to estimate HBV incidence and HBV surface antigen (HBsAg) clearance in HIV-infected adults in Botswana.This was a retrospective longitudinal study of 442 HIV-1C infected treatment naïve patients enrolled in a previous Botswana Harvard AIDS Institute Partnership study. Archived plasma samples from 435 HIV-infected treatment naïve participants were screened for HBsAg and HBV core antibody (anti-HBc). HBsAg was evaluated annually over a 4-year period, and HBV deoxyribonucleic acid (DNA) levels of HBsAg-positive chronic and incident patients were quantified.Baseline median CD4+ T-cell count was 458 cells/μL [Q1, Q3: 373, 593], and median HIV viral load was 4.15 copies/mL [Q1, Q3: 3.46, 4.64]. Twenty two HBV incident cases occurred, representing an incidence of 3.6/100 person-years [95% CI: 2.2-5.6]. All incident HBV cases with a follow-up sample available for screening (13/22) cleared HBsAg. Detectable HBV viral loads among chronic and incident cases ranged between 5.15 × 10 to 1.4 × 10 IU/L and 1.80 × 10 to 1.7 × 10 IU/mL, respectively.We report high HBV incidence associated with elevated HBV DNA levels despite high CD4+ T-cell counts in HIV-infected patients in Botswana. These incidence cases represent a potential source of HBV transmission in the population. Scaling-up of HIV treatment strategies utilizing antiretroviral therapy regimens with anti-HBV activity coupled with screening for HBV infections in households of the HBsAg-positive cases is recommended.

Rationale: Early initiation of antiretroviral therapy (ART) leads to long-term viral suppression, reduces proviral reservoir size, and prolongs time to rebound. Since human immunodeficiency virus (HIV) is a lifelong disease, diagnostic monitoring after confirmed infection is typically not performed; therefore, little is known about the impact of early initiation and long-term ART on the sensitivity of assays that detect HIV antibodies and viral nucleic acid in children and adolescents., Patient Concerns: Here we report 1 case of diagnosed and confirmed perinatal HIV-1C infection with longstanding viral suppression, who subsequently had a negative HIV-1 deoxyribonucleic acid (DNA) test, undetectable antibodies to HIV-1, and high CD4+ T cell count after 14 years of ART., Diagnosis: The patient was diagnosed with HIV in 2002 at 1 and 2 months of age using DNA polymerase chain reaction. At 8 months old, his viral load was 1210 HIV ribonucleic acid (RNA) copies/mL and CD4 T cell count was 3768 cells/mm., Intervention: At the age of 9 months, highly active antiretroviral therapy comprising of zidovudine, nevirapine, and lamivudine was initiated. The patient remained on this treatment for 14 years 11 months and was virally suppressed., Outcomes: At the age of 14 years 4 months, the participant decided to visit a local voluntary HIV testing center, where a rapid HIV test came out negative and the viral load was undetectable (<400 HIV-1 RNA copies/mL). These results led to termination of ART which led to viral rebound within 9 months., Lessons: As more people with early HIV infection initiate early ART in the context of "Test and Treat all" recommendations, aspects of this report may become more commonplace, with both clinical and public health implications. If the possibility of functional cure (or false-positive diagnosis) is being considered, decisions to terminate ART should be made cautiously and with expert guidance, and may benefit from highly sensitive quantification of the proviral reservoir.

Purpose of Review: Botswana, a small country in southern Africa, has had a very high prevalence of HIV since about 1995. It seems important to analyze the response of this country to help us understand how it became one of the first nations to achieve the 90-90-90 targets., Recent Findings: Botswana began a national program for treatment of HIV/AIDS with ARVs in 2002. Initially established in the four largest population centers, it expanded to more than 30 sites throughout the country by 2004. Also in 2004, an 'opt out' system for HIV testing was introduced. The government-sponsored ARV regimen for initiation was ZDV/3TC/EFV until 2008, then TDF/FTC/EFV until 2016, when it became TDF/FTC/DTG along with the introduction of treatment for all. Levels of both acquired and transmitted drug resistance have been low. In late 2013, we began the Ya Tsie or Botswana Combination Prevention Project (BCCP), a cluster randomized trial for 100 000 exurban and rural adults in 30 villages that included enhanced testing, linkage to care, and ARV treatment for 15 intervention villages, one in each pair. A 20% baseline survey in 2013-2015 revealed 29% prevalence and values that were already close to 90-90-90. With 83.3% of HIV-positive adults knowing they were infected, 87.4% of those knowing they were infected already on ARV, and 96.5% of those on ARV in complete viral suppression, this represented a combined value of 70.2% toward the target of 73%. By best estimates, incidence fell by about 30% over the 29-month period of the trial, which is compatible with Botswana reaching a 90% reduction in incidence in 10 years as proposed by the UNAIDS model. On the basis of an end-of-study survey in three intervention villages, we estimate that Botswana could reach 95-95-95 by 2019., Summary: These results illustrate that it is possible to reach 90-90-90 in countries with very high HIV prevalence.

Background: Scale-up of antiretroviral therapy (ART) and introduction of treat-all strategy necessitates population-level monitoring of acquired HIV drug resistance (ADR) and pretreatment drug resistance (PDR) mutations., Methods: Blood samples were collected from 4973 HIV-positive individuals residing in 30 communities across Botswana who participated in the Botswana Combination Prevention Project (BCPP) in 2013-2018. HIV sequences were obtained by long-range HIV genotyping. Major drug-resistance mutations (DRMs) and surveillance drug resistance mutations (SDRMs) associated with nucleoside reverse transcriptase inhibitors (NRTI) and nonnucleoside reverse transcriptase inhibitors (NNRTI) were analyzed according to the Stanford University HIV Drug Resistance Database. Viral sequences were screened for G-to-A hypermutations. A threshold of 2% was used for hypermutation adjustment. Viral suppression was considered at HIV-1 RNA load ≤400 copies/ml., Results: Among 4973 participants with HIV-1C sequences, ART data were available for 4927 (99%) including 3858 (78%) on ART. Among those on ART, 3435 had viral load data and 3297 (96%) were virologically suppressed. Among 1069 (22%) HIV-infected individuals not on ART, we found NRTI-associated and NNRTI-associated SDRMs were found in 1.5% (95% confidence interval [CI] 1.0-2.5%) and 2.9% (95% CI 2.0-4.2%), respectively. Of the 138 (4%) of individuals who had detectable HIV-1 RNA, we found NRTI-associated and NNRTI-associated drug resistance mutations in 16% (95% CI 10-25%) and 33% (95% CI 25-42%), respectively., Conclusion: We found a low prevalence of NRTI-associated and NNRTI-associated PDR-resistance mutations among residents of rural and peri-urban communities across Botswana. However, individuals on ART with detectable virus had ADR NRTI and NNRTI mutations above 15%.

Purpose of Review: HIV-associated cryptococcal meningitis remains a significant contributor to AIDS-related mortality despite widened access to antiretroviral therapy. Even in clinical trial settings 10-week mortality is roughly 40%. A number of important clinical trials have either recently concluded or are actively recruiting., Recent Findings: Global burden of disease estimates suggest cryptococcal meningitis causes 181 100 deaths annually. Screening blood for cryptococcal antigen in HIV-infected individuals with CD4 cell counts less than 100 cells/μl and preemptive antifungal treatment for those with detectable cryptococcal antigen reduces the incidence of cryptococcal meningitis and is likely to reduce mortality. Cryptococcal meningitis treatment with conventional 14-day courses of amphotericin are associated with high toxicity and mortality and can be reduced to 7 days if given alongside flucytosine. Flucytosine is a significantly superior adjunct to amphotericin treatment compared with fluconazole. In settings without amphotericin B dual oral antifungal combinations of flucytosine and fluconazole offer an effective alternative treatment. A single, high-dose of liposomal amphotericin is effective at reducing fungal burden and is being tested in a phase III trial., Summary: Recently completed and ongoing clinical trials are increasing our understanding of how to optimize induction therapy for cryptococcal meningitis. Advocacy efforts are needed to broaden access to amphotericin formulations and flucytosine.

: There are limited data on the effectiveness of dolutegravir (DTG)-based combination antiretroviral therapy (ART) in real-life settings in southern Africa where HIV-1 subtype C predominates. We report a patient infected with HIV-1 subtype C on DTG-based ART previously exposed to raltegravir who developed multidrug resistance mutations to four antiretroviral classes. There is need for drug resistance monitoring and clinical vigilance to ensure effectiveness of HIV treatment programs even in the era of DTG-based ART.

: Among 3596 HIV-positive participants enrolled in the Botswana Combination Prevention Project who self-reported no prior antiretroviral (ARV) therapy use and were tested for viral load (n = 951; 27% of all participants), 136 (14%) had HIV-1 RNA less than 400 copies/ml. ARV drugs were detected in 52 (39%) of 134 participants tested. Adjusting for undisclosed ARV use increased the overall estimate of virally suppressed individuals on ARV therapy by 1.4% from 70.2 to 71.6%.

Objective: Conflicting data exist regarding the impact of in-utero exposure to maternal combination antiretrovirals. We compared neurodevelopmental outcomes between HIV-exposed-uninfected (HEU) children exposed in utero to three-drug combination antiretroviral therapy (ART) vs. zidovudine (ZDV) monotherapy., Design: Prospective study of child neurodevelopment, nested within two cohorts of HIV-infected mothers and their children in Botswana (one observational, one interventional)., Methods: The Tshipidi and Mma Bana studies enrolled HIV-infected women during pregnancy and followed their HEU children for 24 months. Mothers took three-drug ART or ZDV during pregnancy. ART-exposed babies were mostly breastfed, and ZDV-exposed were formula-fed. Neurodevelopmental outcomes, measured at 24 months using Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III) and Development Milestones Checklist (DMC), were compared in adjusted linear regression according to antiretroviral exposure., Results: Of 598 HEU children with valid neurodevelopment assessments, 382 were ART-exposed and 210 were ZDV-exposed. Adjusted mean Bayley-III scores were similar among ART-exposed vs. ZDV-exposed, with adjusted mean differences (95% confidence interval): Bayley-III Cognitive: -0.3 (-1.4, 0.9); Gross Motor: 0.8 (-0.1, 1.7); Fine Motor: 0.5 (-0.2, 1.3); Expressive Language: 0.7 (-0.3, 1.7); Receptive Language: 0.1 (-0.7, 0.8); and DMC Locomotor: 0.0 (-0.5, 0.6); Fine Motor: 0.3 (-0.3, 0.8); Language: -0.1 (-0.5, 0.4); Personal-Social: 0.2 (-0.7, 1.1). Similarly, when restricted to formula-fed children in one cohort (Tshipidi), there were no differences in adjusted mean scores., Conclusion: Neurodevelopmental outcomes at 24 months of age were similar in ART-exposed vs. ZDV-exposed HEU children. Maternal ART with breastfeeding does not appear to have an adverse effect on neurodevelopment.

Objective: To compare the effect of preconception initiation of zidovudine, lamivudine, nevirapine (ZDV/3TC/NVP) versus tenofovir, emtricitabine, efavirenz (TDF/FTC/EFV) on adverse birth outcomes., Design: Emulation of a hypothetical (target) trial using a birth surveillance study in Botswana during an era of CD4-based antiretroviral therapy (ART) initiation., Methods: In women who initiated ART less than 3 years from HIV diagnosis, conceived 0.5-5 years after ART initiation, and delivered at least 24-week gestation, we estimated risk ratios for stillbirth, preterm delivery (<37 weeks), very preterm delivery (<32 weeks), small-for-gestational-age (SGA) (<10 percentile), very SGA (<3 percentile), and any adverse or severe birth outcome for first-line ZDV/3TC/NVP versus TDF/FTC/EFV. We conducted a historical comparison in women who initiated TDF/FTC/EFV in 2012-2015 and ZDV/3TC/NVP in 2004-2011, and a contemporaneous comparison in an era of overlapping use from 2009 to 2013., Results: In the historical comparison, 1108 women initiated TDF/FTC/EFV and 637 initiated ZDV/3TC/NVP. In the contemporaneous comparison, 1052 initiated TDF/FTC/EFV and 298 initiated ZDV/3TC/NVP. TDF/FTC/EFV initiators were younger and more likely to be nulliparous than ZDV/3TC/NVP initiators in both comparisons. In the historical comparison, the adjusted risk ratios (95% confidence interval) comparing ZDV/3TC/NVP with TDF/FTC/EFV were 2.95 (1.76, 4.96) for stillbirth, 1.40 (1.17, 1.67) for preterm delivery, 2.58 (1.70, 3.91) for very preterm delivery, 1.96 (1.64, 2.34) for SGA, 2.32 (1.73, 3.09) for very SGA, 1.54 (1.38, 1.72) for any adverse birth outcome, and 2.20 (1.76, 2.75) for any severe birth outcome, and were similar in the contemporaneous comparison., Conclusion: Preconception initiation of ZDV/3TC/NVP compared with TDF/FTC/EFV may increase the risk of adverse birth outcomes.

Intrahost human immunodeficiency virus (HIV)-1 diversity increases linearly over time. We assessed the extent to which mean pairwise distances and the time to the most recent common ancestor (tMRCA) inferred from intrahost HIV-1C env sequences were associated with the estimated time of HIV infection. Data from a primary HIV-1C infection study in Botswana were used for this analysis (N = 42). A total of 2540 HIV-1C env gp120 variable loop region 1 to conserved region 5 (V1C5) of the HIV-1 envelope gp120 viral sequences were generated by single genome amplification and sequencing, with an average of 61 viral sequences per participant and 11 sequences per time point per participant. Raw pairwise distances were calculated for each time point and participant using the ape package in R software. The tMRCA was estimated using phylogenetic inference implemented in Bayesian Evolutionary Analysis by Sampling Trees v1.8.2. Pairwise distances and tMRCA were significantly associated with the estimated time since HIV infection (both P < 0.001). Taking into account multiplicity of HIV infection strengthened these associations. HIV-1C env-based pairwise distances and tMRCA can be used as potential markers for HIV recency. However, the tMRCA estimates demonstrated no advantage over the pairwise distances estimates.