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Background: We evaluated the association of inflammation and dysbosis on cervicovaginal fluid (CVF) tenofovir (TFV) concentrations in women taking oral tenofovir disoproxil fumarate/emtricitable for HIV pre-exposure prophylaxis (PrEP) in the United States., Setting: Thirty-five women in a HIV PrEP implementation study attended their week 24 visit at a San Diego research clinic and provided CVF specimens., Methods: Women in the Adherence Enhancement Guided by Individualized Texting and Drug Levels study had their CVF specimens evaluated for (1) sexually transmitted bacterial (Neisseria gonorrhoeae, Chlamydia trachomatis, Gardnerella, and Trichomonas vaginalis), viral (human papillomavirus, cytomegalovirus and herpes simplex virus-1/2) and fungal (Candida) infections; (2) microbiome composition by 16 S sequencing (V3-V4 region); and (3) cytokine profiles by enzyme-linked immunoassay (Interleukin-8, macrophage Inflammatory protein-1a, macrophage Inflammatory Protein-1b and interferon-γ-inducible protein-10). Univariate statistical analysis was used to determine factors associated with CVF TFV concentrations. CVF TFV of 100-1000 ng/mL benchmarked typical genital concentrations and TFV-diphosphate in dried blood spots of 700 fmol/punch was considered adequate adherence., Results: Thirty-five women had CVF specimens collected. No factor was associated with CVF TFV concentrations or discordance of blood and vaginal concentrations. Among 27 participants assessed for vaginosis (Candida, Gardnerella or Trichomonas), women with Gardnerella (n = 11) were more likely to have high (>1000 ng/mL) CVF TFV concentrations (82% versus 33%, P = 0.02)., Conclusions: Presence of genital viruses, cytokines, or vaginal community state types were not associated with low CVF TFV concentrations in cisgender women taking oral tenofovir disoproxil fumarate/emtricitable for PrEP. The surprising association observed between presence of Gardnerella and higher vaginal TFV concentrations needs further evaluation., Competing Interests: M.K. has research funding paid to the institution from Gilead Sciences and ViiV Healthcare. J.B. has research funding paid to the institution from Gilead Sciences. P.L.A. has received personal fees and research funding paid to his institution from Gilead Sciences. S.R.M. has research funding paid to the institution from Gilead Sciences and Merck. S.R.M. has financial interests in Bristol Myers Sqibb, Geron, Pfizer and Aspera Biomedicines and has acted as consultant to Primmune Therapeutics. The remaining authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: People living with HIV (PLWH) experience increased risk of Hodgkin lymphoma (HL) despite effective initiation of antiretroviral therapy (ART). In high-income countries, outcomes following HIV HL have been reported to be non-differential, or inferior for PLWH. We sought to assess the effect of HIV on HL survival in Botswana, an African country with a generalized HIV epidemic and high ART coverage, to describe a context more reflective of global HIV populations., Patients and Methods: In the Thabatse Cancer Cohort, consenting participants initiating treatment for HL at one of four cancer centers in Botswana were enrolled from 2010 to 2020. Patients were followed quarterly for up to 5 years. The impact of HIV on survival following treatment initiation was assessed using an inverse probability-weighted Cox marginal structural model adjusted for age, performance status, and disease stage., Results: Seventy-eight new HL cases were enrolled, 47 (60%) were PLWH and 31 (40%) were HIV-uninfected. Baseline characteristics were similar between groups. The majority (61%) of patients presented with regional disease (stage I or II) with no statistically significant difference by HIV status ( P = .38). Nearly all (87%) PLWH participants were on ART before their HL diagnosis (median ART duration 42 months), and median CD4 count was 413 cells/μL (interquartile range 253-691). Survival, in unadjusted analyses, was lower among patients without HIV compared with PLWH (log rank P = .021). In adjusted analysis, HIV infection was not significantly associated with survival in inverse probability-weighted Cox model (hazard ratio 0.43; 95% CI, 0.16 to 1.16; P = .094)., Conclusion: In this cohort of patients treated for HL in Botswana, survival in PLWH (87% on long-standing ART) was at least as good as in individuals without HIV., Competing Interests: Aliyah SohaniConsulting or Advisory Role: AbbVie, MersanaExpert Testimony: Levin Papantonio Jason EfstathiouConsulting or Advisory Role: Blue Earth Diagnostics, AstraZeneca, Boston Scientific, Roivant, Merck, Myovant Sciences Philippe ArmandHonoraria: Merck, Bristol Myers SquibbConsulting or Advisory Role: Bristol Myers Squibb, Merck Sharp & Dohme, ADC Therapeutics, Celgene, Daiichi Sankyo, C4 Therapeutics, GenMab, Miltenyi Biotec, Enterome, Tessa Therapeutics, MorphoSys, Regeneron, Genentech/Roche, EpizymeResearch Funding: Merck Sharp & Dohme (Inst), Bristol Myers Squibb (Inst), Roche (Inst), Adaptive Biotechnologies (Inst), Affimed Therapeutics (Inst), Genentech (Inst), IGM (Inst), Kite, a Gilead Company (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Merck Sharp & Dohme Scott Dryden-PetersonPatents, Royalties, Other Intellectual Property: Royalties received from UpToDate, Inc for article on HIVNo other potential conflicts of interest were reported.

Persistent inflammation occurs in people with HIV (PWH) and has many downstream adverse effects including myocardial infarction, neurocognitive impairment and death. Because the proportion of people with HIV who use cannabis is high and cannabis may be anti-inflammatory, it is important to characterize the impact of cannabis use on inflammation specifically in PWH. We performed a selective, non-exhaustive review of the literature on the effects of cannabis on inflammation in PWH. Research in this area suggests that cannabinoids are anti-inflammatory in the setting of HIV. Anti-inflammatory actions are mediated in many cases through effects on the endocannabinoid system (ECS) in the gut, and through stabilization of gut-blood barrier integrity. Cannabidiol may be particularly important as an anti-inflammatory cannabinoid. Cannabis may provide a beneficial intervention to reduce morbidity related to inflammation in PWH.

People living with HIV infection (PWH) disclose that cannabis is an effective strategy for alleviating symptoms associated with HIV disease. However, some medical providers feel ill-informed to engage in evidence-based conversations. HIV leads to alterations in the gut microbiome, gut-brain axis signaling, and chronic inflammation. The endocannabinoid system regulates homeostasis of multiple organ systems. When deficient, dysregulation of the gut-brain axis can result in chronic inflammation and neuroinflammation. Cannabis along with the naturally occurring endocannabinoids has antioxidant and anti-inflammatory properties that can support healing and restoration as an adjunctive therapy. The purpose of this literature review is to report the physiologic mechanisms that occur in the pathology of HIV and discuss potential benefits of cannabinoids in supporting health and reducing the negative effects of comorbidities in PWH., Competing Interests: No competing financial interests exist., (Copyright 2021, Mary Ann Liebert, Inc., publishers.)

The biological mechanisms underlying emotional distress in HIV infection are likely to be complex but remain understudied. We investigated whether dysbiotic signatures in the gut microbiome of persons living with HIV (PLWH) are associated with their emotional status. We retrospectively examined the gut microbiome and clinical evaluation of 129 adults (94 PLWH and 35 HIV-) enrolled at UC San Diego's HIV Neurobehavioral Research Program. A subset of participants (32 PLWH vs. 13 HIV-) underwent an emotional assessment using the NIH Toolbox Emotion Battery summarized by three composite scores (negative affect, social satisfaction, and psychological well-being). We then sequenced the 16S rDNA V3-V4 regions from stool and performed taxonomic assignment using CLC Microbial Genomics Module. The gut microbiota profiles were evaluated in relation to participants' emotional assessment. All analyses were done in R statistical software. We found that the relative abundance of aerotolerant bacteria was significantly higher in PLWH (p < 0.01) and was associated with a lifetime major depression diagnosis independently of HIV status (p = 0.05). Moreover, PLWH experienced significantly worse psychological well-being (p = 0.02), less social satisfaction (p = 0.03), and more negative affect (p = 0.02). Higher levels of aerotolerant bacteria were associated with worse psychological well-being (rho = -0.35, p = 0.02), less social satisfaction (r = - 0.42, p < 0.01), and more negative affect (rho = 0.46, p < 0.01). The association of aerotolerant bacteria with social satisfaction and negative affect was independent of HIV status (p < 0.05, for both). The over-representation of aerotolerant bacteria in the gut may reflect worse oxidative stress and barrier defects and may contribute to emotional distress during HIV infection.

Objective: To determine whether cannabis may reduce HIV-related persistent inflammation, we evaluated the relationship of cannabis use in people with HIV (PWH) to inflammatory cytokines in CSF and blood plasma., Methods: We measured a panel of proinflammatory cytokines (interleukin [IL]-16, C-reactive protein [CRP], IL-6, interferon gamma-induced protein [IP]-10, soluble CD14, and soluble tumor necrosis factor receptor type II [sTNFRII]) in CSF and blood plasma in PWH and HIV- individuals who did or did not use cannabis at various levels of exposure. Participants in this observational cohort were recruited from community sources and underwent lumbar puncture and phlebotomy. Cannabis use parameters were characterized by self-report based on a semistructured timeline follow-back interview. Cytokines were measured using commercially available immunoassays. Data were analyzed using factor analysis., Results: Participants were 35 PWH and 21 HIV- individuals, mean (SD) age 45.4 (14.5) years, 41 cannabis ever users, and 15 never users. PWH and HIV- were not different in recency, cumulative months, grams, or density of cannabis use. A factor analysis using CSF biomarkers yielded a factor loading on CRP, IL-16, and sTNFRII that was significantly associated with recency of cannabis use (more recent use associated with lower factor 1 values, reflecting less inflammation; r = 0.331 [95% CI 0.0175, 0.586]). In particular, more recent cannabis use was related to lower IL-16 levels (r = 0.549 [0.282, 0.737]). Plasma biomarkers yielded a factor loading on sTNFRII and IP-10 that was associated with more recent cannabis use (more recent use related to less inflammation; r = 0.374 [0.0660, 0.617])., Conclusions: Recent cannabis use was associated with lower levels of inflammatory biomarkers, both in CSF and blood, but in different patterns. These results are consistent with compartmentalization of immune effects of cannabis. The principal active components of cannabis are highly lipid soluble and sequestered in brain tissue; thus, our findings are consistent with specific anti-neuroinflammatory effects that may benefit HIV neurologic dysfunction., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Botswana is close to reaching the UNAIDS "90-90-90" HIV testing, antiretroviral treatment (ART), and viral suppression goals. We sought to determine HIV incidence in this setting with both high HIV prevalence and high ART coverage., Methods: We used a cross-sectional approach to assessing HIV incidence. A random, population-based sample of adults age 16-64 years was enrolled in 30 rural and peri-urban communities as part of the Botswana Combination Prevention Project (BCPP), from October 2013 -November 2015. Data and samples from the baseline household survey were used to estimate cross-sectional HIV incidence, following an algorithm that combined Limiting-Antigen Avidity Assay (LAg-Avidity EIA), ART status (documented or by testing ARV drugs in plasma) and HIV-1 RNA load. The LAg-Avidity EIA cut-off normalized optical density (ODn) was set at 1.5. The HIV-1 RNA cut-off was set at 400 copies/mL. For estimation purposes, the Mean Duration of Recent Infection was 130 days and the False Recent Rate (FRR) was evaluated at values of either 0 or 0.39%., Results: Among 12,610 individuals participating in the baseline household survey, HIV status was available for 12,570 participants and 3,596 of them were HIV positive. LAg-Avidity EIA data was generated for 3,581 (99.6%) of HIV-positive participants. Of 326 participants with ODn ≤1.5, 278 individuals were receiving ART verified through documentation and were considered to represent longstanding HIV infections. Among the remaining 48 participants who reported no use of ART, 14 had an HIV-1 RNA load ≤400 copies/mL (including 3 participants with ARVs in plasma) and were excluded, as potential elite/viremic controllers or undisclosed ART. Thus, 34 LAg-Avidity-EIA-recent, ARV-naïve individuals with detectable HIV-1 RNA (>400 copies/mL) were classified as individuals with recent HIV infections. The annualized HIV incidence among 16-64 year old adults was estimated at 1.06% (95% CI 0.68-1.45%) with zero FRR, and at 0.64% (95% CI 0.24-1.04%) using a previously defined FRR of 0.39%. Within a subset of younger individuals 16-49 years old, the annualized HIV incidence was estimated at 1.29% (95% CI 0.82-1.77%) with zero FRR, and at 0.90% (95% CI 0.42-1.38%) with FRR set to 0.39%., Conclusions: Using a cross-sectional estimate of HIV incidence from 2013-2015, we found that at the time of near achievement of the UNAIDS 90-90-90 targets, ~1% of adults (age 16-64 years) in Botswana's rural and peri-urban communities became HIV infected annually., Competing Interests: Kara Bennett is employed by Bennett Statistical Consulting, Inc and Jean Leidner was employed by Goodtables Data Consulting. The entities above provided support in the form of salaries for authors Kara Bennett and Jean Leidner, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose: Botswana has a high prevalence of HIV infection. Currently, there are few data regarding the sociodemographic factors, clinical characteristics, and outcomes of non-Hodgkin lymphoma (NHL)-an AIDS-defining cancer-in the country., Patients and Methods: This study used a prospective cancer registry to identify patients with a new diagnosis of NHL reporting for specialty cancer care at three hospitals in Botswana between October 2010 and August 2016. Treatment patterns and clinical outcomes were analyzed., Results: One hundred four patients with a new diagnosis of NHL were enrolled in this study, 72% of whom had HIV infection. Compared with patients not infected with HIV, patients infected with HIV were younger (median age, 53.9 v 39.1 years; P = .001) and more likely to present with an aggressive subtype of NHL (65.5% v 84.0%; P = .008). All patients infected with HIV received combined antiretroviral therapy throughout the course of the study, and similar chemotherapeutic regimens were recommended for all patients, regardless of subtype or HIV status (six to eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone; or cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab). There was no difference in 1-year mortality among patients not infected with HIV and patients infected with HIV (unadjusted analysis, 52.9% v 37.1%; hazard ratio [HR], 0.73; P = .33; adjusted analysis, HR, 0.57; P = .14). However, when compared with a cohort of patients in the United States matched by subtype, stage, age, sex, and race, patients in Botswana fared worse (1-year mortality, 22.8% v 46.3%; HR, 1.89; P = .001)., Conclusion: Among patients with NHL reporting for specialty cancer care in Botswana, there is no association between HIV status and 1-year survival.

Background: HIV-1 RNA load is the best biological predictor of HIV transmission and treatment response. The rate of virologic suppression among key subpopulations can guide HIV prevention programs., Methods: The Botswana Combination Prevention Project performed a population-based household survey among adults in 30 communities in Botswana. Data collected included knowledge of HIV-positive status, antiretroviral therapy (ART) coverage, and virologic suppression (HIV-1 RNA ≤400 copies per milliliter). Individuals aged 16-29 years were considered young adults., Results: Among 552 young people living with HIV enrolled with RNA load data and ART status available, 51% (n = 279) had undetectable HIV-1 RNA, including 54% of young women and 32% of young men [sex prevalence ratio (PR): 0.53; 95% confidence interval (CI): 0.43 to 0.80; P < 0.001]. Compared with older adults (30-64 years old), young HIV-infected adults were significantly less likely to have undetectable HIV-1 RNA (PR: 0.65; 95% CI: 0.59 to 0.70; P < 0.0001), including both men (PR: 0.43; 95% CI: 0.34 to 0.56; P < 0.0001) and women (PR: 0.67; 95% CI: 0.62 to 0.74; P < 0.0001). Among a subset of people living with HIV receiving ART, young adults also were less likely to have undetectable HIV-1 RNA load than older adults (PR: 0.93; 95% CI: 0.90 to 0.95; P = <0.0001). Analysis of the care continuum revealed that inferior HIV diagnosis and suboptimal linkage to care are the primary reasons for low virologic suppression among young adults., Conclusions: Young adults in Botswana are significantly less likely to have undetectable HIV-1 RNA load compared with older adults. In the era of broad scale-up of ART, interventions able to diagnose young adults living with HIV and link them to effective therapy are urgently needed.

Background: Three-quarters of cancer deaths occur in resource-limited countries, and delayed presentation contributes to poor outcome. In Botswana, where more than half of cancers arise in HIV-infected individuals, we sought to explore predictors of timely oncology care and evaluate the hypothesis that engagement in longitudinal HIV care improves access., Methods: Consenting patients presenting for oncology care from October 2010 to September 2014 were interviewed and their records were reviewed. Cox and logistic models were used to examine the effect of HIV and other predictors on time to oncology care and presentation with advanced cancer (stage III or IV)., Results: Of the 1,146 patients analyzed, 584 (51%) had HIV and 615 (54%) had advanced cancer. The initial clinic visit occurred a mean of 144 days (median 29, interquartile range 0-185) after symptom onset, but subsequent mean time to oncology care was 406 days (median 160, interquartile range 59-653). HIV status was not significantly associated with time to oncology care (adjusted hazard ratio [aHR] 0.91, 95% confidence interval [CI] 0.79-1.06). However, patients who reported using traditional medicine/healers engaged in oncology care significantly faster (aHR 1.23, 95% CI 1.09-1.40) and those with advanced cancer entered care earlier (aHR 1.48, 95% CI 1.30-1.70). Factors significantly associated with advanced cancer included income <$50 per month (adjusted odds ratio [aOR] 1.35, 95% CI 1.05-1.75), male sex (aOR 1.45, 95% CI 1.12-1.87), and pain as the presenting symptom (aOR 1.39, 95% CI 1.03-1.88)., Conclusion: Longitudinal HIV care did not reduce the substantial delay to cancer treatment. Research focused on reducing health system delay through coordination and navigation is needed., Implications for Practice: The majority (54%) of patients in this large cohort from Botswana presented with advanced-stage cancer despite universal access to free health care. Median time from first symptom to specialized oncology care was 13 months. For HIV-infected patients (51% of total), regular longitudinal contact with the health system, through quarterly doctor visits for HIV management, was not successful in providing faster linkages into oncology care. However, patients who used traditional medicine/healers engaged in cancer care faster, indicating potential for leveraging traditional healers as partners in early cancer detection. New strategies are urgently needed to facilitate diagnosis and timely treatment of cancer in low- and middle-income countries., (©AlphaMed Press.)

Background: Before introduction of tenofovir/emtricitabine/efavirenz (TDF/FTC/EFV), 3-drug antiretroviral therapy (ART) was associated with increased adverse birth outcomes when used for prevention of mother-to-child HIV transmission (PMTCT) in Botswana., Methods: We extracted obstetric records from all women at the 2 largest maternities in Botswana from 2009-2011 when Botswana National Guidelines recommended zidovudine (ZDV) from 28 weeks gestational age (GA) for CD4 ≥350 and ART for CD4 <350, and again in 2013-2014 after implementation of TDF/FTC/EFV for prevention of mother-to-child HIV transmission regardless of CD4 or GA. We compared the use of TDF/FTC/EFV in pregnancy with other 3-drug ART regimens, and with initiation of ZDV, among women with similar CD4 cell counts. Outcomes included small for gestational age (SGA), preterm delivery (PTD) (<37 weeks GA), and stillbirths (SB)., Results: Among 9445 HIV-infected women delivering during the study period, 170 were on TDF/FTC/EFV at conception and 1468 initiated TDF/FTC/EFV during pregnancy. Adverse birth outcomes were high overall (3% SB, 21% PTD, and 18% SGA) and among women receiving TDF/FTC/EFV (3% SB, 22% PTD, and 12% SGA). There was no difference in PTD or SB among women initiating TDF/FTC/EFV compared with ZDV or other 3-drug ART, but initiating TDF/FTC/EFV was associated with fewer SGA infants than other 3-drug ART (adjusted odds ratio: 0.4, 95% confidence interval: 0.2 to 0.7)., Conclusions: Adverse birth outcomes remain high among HIV-infected women. TDF/FTC/EFV was at least as safe as other ART and associated with fewer SGA infants when initiated during pregnancy. Larger studies are needed to evaluate birth outcomes and congenital abnormalities among women on TDF/FTC/EFV at conception.

Background: The expansion of combination antiretroviral treatment (ART) in southern Africa has dramatically reduced mortality due to AIDS-related infections, but the impact of ART on cancer incidence in the region is unknown. We sought to describe trends in cancer incidence in Botswana during implementation of the first public ART program in Africa., Methods: We included 8479 incident cases from the Botswana National Cancer Registry during a period of significant ART expansion in Botswana, 2003-2008, when ART coverage increased from 7.3% to 82.3%. We fit Poisson models of age-adjusted cancer incidence and counts in the total population, and in an inverse probability weighted population with known HIV status, over time and estimated ART coverage., Findings: During this period 61.6% of cancers were diagnosed in HIV-infected individuals and 45.4% of all cancers in men and 36.4% of all cancers in women were attributable to HIV. Age-adjusted cancer incidence decreased in the HIV infected population by 8.3% per year (95% CI -14.1 to -2.1%). However, with a progressively larger and older HIV population the annual number of cancers diagnosed remained constant (0.0% annually, 95% CI -4.3 to +4.6%). In the overall population, incidence of Kaposi's sarcoma decreased (4.6% annually, 95% CI -6.9 to -2.2), but incidence of non-Hodgkin lymphoma (+11.5% annually, 95% CI +6.3 to +17.0%) and HPV-associated cancers increased (+3.9% annually, 95% CI +1.4 to +6.5%). Age-adjusted cancer incidence among individuals without HIV increased 7.5% per year (95% CI +1.4 to +15.2%)., Interpretation: Expansion of ART in Botswana was associated with decreased age-specific cancer risk. However, an expanding and aging population contributed to continued high numbers of incident cancers in the HIV population. Increased capacity for early detection and treatment of HIV-associated cancer needs to be a new priority for programs in Africa.

: Botswana was one of the first African countries to transition from WHO Option A to Option B for prevention of mother-to-child HIV transmission (MTCT). We evaluated the impact of this transition on projected MTCT risk through review of 10,681 obstetric records of HIV-infected women delivering at 6 maternity wards. Compared with Option A, women receiving antenatal care under Option B were more likely to receive combination antiretroviral therapy (ART), adjusted odds ratio (aOR): 2.59 (95% confidence interval: 2.25 to 2.98), but they were also more likely to receive no antenatal antiretrovirals, aOR: 2.10 (95% confidence interval: 1.74 to 2.53). Consequently, initial implementation of Option B was associated with increased projected MTCT at 6 months of age, 3.79% under Option A and 4.69% under Option B (P < 0.001). Successful implementation of Option B or B+ may require that ART can be initiated within antenatal clinics, and novel strategies to remove barriers to rapid ART initiation.

Background: Less than one-third of HIV-infected pregnant women eligible for combination antiretroviral therapy (ART) globally initiate treatment prior to delivery, with lack of access to timely CD4 results being a principal barrier. We evaluated the effectiveness of an SMS-based intervention to improve access to timely antenatal ART., Methods: We conducted a stepped-wedge cluster randomized trial of a low-cost programmatic intervention in 20 antenatal clinics in Gaborone, Botswana. From July 2011-April 2012, 2 clinics were randomly selected every 4 weeks to receive an ongoing clinic-based educational intervention to improve CD4 collection and to receive CD4 results via an automated SMS platform with active patient tracing. CD4 testing before 26 weeks gestation and ART initiation before 30 weeks gestation were assessed., Results: Three-hundred-sixty-six ART-naïve women were included, 189 registering for antenatal care under Intervention and 177 under Usual Care periods. Of CD4-eligible women, 100 (59.2%) women under Intervention and 79 (50.6%) women under Usual Care completed CD4 phlebotomy before 26 weeks gestation, adjusted odds ratio (aOR, adjusted for time that a clinic initiated Intervention) 0.87 (95% confidence interval [CI]0.47-1.63, P = 0.67). The SMS-based platform reduced time to clinic receipt of CD4 test result from median of 16 to 6 days (P<0.001), was appreciated by clinic staff, and was associated with reduced operational cost. However, rates of ART initiation remained low, with 56 (36.4%) women registering under Intervention versus 37 (24.2%) women under Usual Care initiating ART prior to 30 weeks gestation, aOR 1.06 (95%CI 0.53-2.13, P = 0.87)., Conclusions: The augmented SMS-based intervention delivered CD4 results more rapidly and efficiently, and this type of SMS-based results delivery platform may be useful for a variety of tests and settings. However, the intervention did not appear to improve access to timely antenatal CD4 testing or ART initiation, as obstacles other than CD4 impeded ART initiation during pregnancy.

Background: Prophylactic cotrimoxazole is recommended for infants born to HIV-infected mothers. However, cotrimoxazole may increase the risk of severe anemia or neutropenia., Methods: We compared the proportion of HIV-exposed uninfected (HIV-EU) infants experiencing incident severe anemia (and separately, severe neutropenia) between a prospective cohort receiving prophylactic cotrimoxazole from 1 to 6 months vs. infants from two prior trials who did not receive cotrimoxazole. Infants were from rural and urban communities in southern Botswana., Results: A total of 1705 HIV-EU infants were included. Among these 645 (37.8%) were fed with iron-supplemented formula from birth. Severe anemia developed in 87 (5.1%) infants, and severe neutropenia in 164 (9.6%) infants. In an analysis stratified by infant feeding method, there were no significant differences in the risk of severe anemia by prophylactic cotrimoxazole exposure-risk difference, -0.69% (95% confidence interval [CI] -2.1 to 0.76%). Findings were similar in multivariable analysis, adjusted odds ratio (aOR) 0.35 (95% CI 0.07 to 1.65). There were also no significant differences observed for severe neutropenia by cotrimoxazole exposure, risk difference 2.0% (95% CI -1.3 to 5.2%) and aOR 0.80 (95% CI 0.33 to 1.93)., Conclusions: Severe anemia and severe neutropenia were infrequent among HIV-exposed uninfected infants receiving cotrimoxazole from 1-6 months of age. Concerns regarding hematologic toxicity should not limit the use of prophylactic cotrimoxazole in HIV-exposed uninfected infants. CLINICALTRIAL.SGOV REGISTRATION NUMBERS: NCT01086878 (http://clinicaltrials.gov/show/NCT01086878), NCT00197587 (http://clinicaltrials.gov/show/NCT00197587), and NCT00270296 (http://clinicaltrials.gov/show/NCT00270296).

Few studies have compared the programmatic effectiveness of the recommended strategies of antenatal highly active antiretroviral therapy (HAART) and zidovudine for prevention of mother-to-child transmission. We prospectively followed infants (93% formula fed) whose mothers who took either HAART (258 infants) or zidovudine (170 infants) during pregnancy in the Botswana national program. Overall, 10 infants (2.5%) acquired HIV--9 infants in the zidovudine group (5.5%, 95% confidence interval: 2.6% to 10.2%) and 1 infant in the HAART group (0.4%, 95% confidence interval: 0.0% to 2.2%). Maternal HAART was associated with decreased prevention of mother-to-child transmission (P = 0.001) and improved HIV-free survival (P = 0.040) compared with zidovudine (with or without single-dose nevirapine) in a programmatic setting.

Background: Maternal highly-active antiretroviral therapy (HAART) reduces mother-to-child HIV transmission but may increase the risk for infant anemia., Methods: The incidence of first severe anemia (grade 3 or 4, Division of AIDS 2004 Toxicity Table) was assessed among HIV-uninfected infants in the Mashi and Mma Bana mother-to-child HIV transmission prevention trials in Botswana. Severe anemia rates were compared between 3 groups: infants exposed to maternal HAART in utero and during breastfeeding (BF) and 1 month of postnatal zidovudine (ZDV) (HAART-BF); infants exposed to maternal ZDV in utero, 6 months of postnatal ZDV, and BF (ZDV-BF); and infants exposed to maternal ZDV in utero, 1 month of postnatal ZDV, and formula-feeding (ZDV-FF)., Results: A total of 1719 infants were analyzed-691 HAART-BF, 503 ZDV-BF, and 525 ZDV-FF. Severe anemia was detected in 118 infants (7.4%). By 6 months, 12.5% of HAART-BF infants experienced severe anemia, compared with 5.3% of ZDV-BF (P < 0.001) and 2.5% of ZDV-FF infants (P < 0.001). In adjusted analysis, HAART-BF infants were at greater risk of severe anemia than ZDV-BF or ZDV-FF infants (adjusted odds ratios 2.6 and 5.8, respectively; P < 0.001). Most anemias were asymptomatic and improved with iron/multivitamin supplementation and cessation of ZDV exposure. However, 11 infants (0.6% of all infants) required transfusion for symptomatic anemia. Microcytosis and hypochromia were common among infants with severe anemia., Conclusions: Exposure to maternal HAART starting in utero was associated with severe infant anemia. Confirmation of this finding and possible strategies to mitigate hematologic toxicity warrant further study.

Background: The impact of in utero exposure to highly active antiretroviral therapy (HAART) on longitudinal growth of HIV-uninfected infants is unknown., Methods: The Mashi and Mma Bana PMTCT intervention trials enrolled HIV-infected pregnant women at four sites in Botswana. Breast-fed (BF), HIV-uninfected infants born at 37 weeks or greater were included in this analysis. Weight-for-age (WAZ), length-for-age (LAZ), and weight-for-length (WLZ) z-scores were calculated using World Health Organization Child Growth Standards. Mean z-scores were compared between in utero antiretroviral exposure groups using Student t test, response profiles analysis, and general linear mixed effects modeling., Results: Growth of 619 HAART-exposed and 440 zidovudine-exposed, HIV-uninfected infants was evaluated. Mean birth weights were 3.01 kg for HAART and 3.15 kg for zidovudine-exposed infants (P < 0.001) with lower mean birth WAZ, length-for-age (LAZ), and weight-for-length (WLZ) among HAART-exposed infants (all P < 0.001). HAART-exposed infants had greater improvement in WAZ and weight-for-length (WLZ) from birth through 2 months (P = 0.03, P < 0.001, respectively). The WAZ did not differ between groups from 3 through 6 months (P = 0.26). Length-for-age (LAZ) remained lower in HAART-exposed infants but the incidence of wasting or stunting did not differ between exposure groups., Conclusions: Lower weights in HAART-exposed uninfected infants at birth were rapidly corrected during the first 6 months of life.

Background: Botswana has the most comprehensive public program in Africa for providing antiretroviral therapy to treat HIV and prevent mother-to-child transmission (PMTCT). Botswana guidelines prioritize CD4(+) cell count testing during pregnancy and initiation of highly active antiretroviral treatment (HAART) for women who qualify for treatment. We analyzed rates of HIV testing, CD4 cell count testing, and HAART initiation during pregnancy., Methods: From October 2007 through June 2008, we reviewed obstetric and laboratory records of women at Princess Marina Hospital in Gaborone, Botswana., Results: We recorded information from 3056 women. Of 2675 women eligible for the PMTCT program, 2623 (98%) had a documented HIV status, of whom 793 (30%) were HIV infected. Among women who were treatment naive at pregnancy conception, 397 (59%) had recorded CD4(+) cell counts, of whom 62 (16%) had a CD4(+) cell count <200 cells per cubic millimeter. Among this subset, 23 (37%) initiated HAART during pregnancy, 26 (42%) received zidovudine prophylaxis, and 13 (21%) received no therapy., Conclusions: We observed low rates of CD4(+) cell count testing and HAART initiation during pregnancy. Antenatal clinics should prioritize CD4(+) cell count testing and referral of women who qualify for HAART to maximize benefits of maternal treatment and PMTCT.

An estimated 38 million people live with human immunodeficiency virus (HIV) worldwide and are at excess risk for multiple cancer types. Elevated cancer risks in people living with HIV (PLWH) are driven primarily by increased exposure to carcinogens, most notably oncogenic viruses acquired through shared transmission routes, plus acceleration of viral carcinogenesis by HIV-related immunosuppression. In the era of widespread antiretroviral therapy (ART), life expectancy of PLWH has increased, with cancer now a leading cause of co-morbidity and death. Furthermore, the types of cancers occurring among PLWH are shifting over time and vary in their relative burden in different parts of the world. In this context, the International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI) convened a meeting in September 2022 of multinational and multidisciplinary experts to focus on cancer in PLWH. This report summarizes the proceedings, including a review of the state of the science of cancer descriptive epidemiology, etiology, molecular tumor characterization, primary and secondary prevention, treatment disparities and survival in PLWH around the world. A consensus of key research priorities and recommendations in these domains is also presented.

BackgroundWe evaluated the association of inflammation and dysbosis on cervicovaginal fluid (CVF) tenofovir (TFV) concentrations in women taking oral tenofovir disoproxil fumarate/emtricitable for HIV pre-exposure prophylaxis (PrEP) in the United States.SettingThirty-five women in a HIV PrEP implementation study attended their week 24 visit at a San Diego research clinic and provided CVF specimens.MethodsWomen in the Adherence Enhancement Guided by Individualized Texting and Drug Levels study had their CVF specimens evaluated for (1) sexually transmitted bacterial (Neisseria gonorrhoeae, Chlamydia trachomatis, Gardnerella, and Trichomonas vaginalis), viral (human papillomavirus, cytomegalovirus and herpes simplex virus-1/2) and fungal (Candida) infections; (2) microbiome composition by 16 S sequencing (V3-V4 region); and (3) cytokine profiles by enzyme-linked immunoassay (Interleukin-8, macrophage Inflammatory protein-1a, macrophage Inflammatory Protein-1b and interferon-γ-inducible protein-10). Univariate statistical analysis was used to determine factors associated with CVF TFV concentrations. CVF TFV of 100-1000 ng/mL benchmarked typical genital concentrations and TFV-diphosphate in dried blood spots of 700 fmol/punch was considered adequate adherence.ResultsThirty-five women had CVF specimens collected. No factor was associated with CVF TFV concentrations or discordance of blood and vaginal concentrations. Among 27 participants assessed for vaginosis (Candida, Gardnerella or Trichomonas), women with Gardnerella (n = 11) were more likely to have high (>1000 ng/mL) CVF TFV concentrations (82% versus 33%, P = 0.02).ConclusionsPresence of genital viruses, cytokines, or vaginal community state types were not associated with low CVF TFV concentrations in cisgender women taking oral tenofovir disoproxil fumarate/emtricitable for PrEP. The surprising association observed between presence of Gardnerella and higher vaginal TFV concentrations needs further evaluation.

BackgroundHuman immunodeficiency virus (HIV) infection leads to blood-brain barrier (BBB) dysfunction that does not resolve despite viral suppression on antiretroviral therapy (ART) and is associated with adverse clinical outcomes. In preclinical models, cannabis restores BBB integrity.MethodsWe studied persons with HIV (PWH) and HIV-negative (HIV-) individuals who had used cannabis recently. We assessed 2 biomarkers of BBB permeability: the cerebrospinal fluid (CSF) to serum albumin ratio (CSAR) and CSF levels of soluble urokinase plasminogen activator receptor (suPAR), a receptor for uPA, a matrix-degrading proteolytic enzyme that disrupts the BBB. A composite index of the BBB markers was created using principal components analysis. Neural injury was assessed using neurofilament light (NFL) in CSF by immunoassay.ResultsParticipants were 45 PWH and 30 HIV- individuals of similar age and ethnicity. Among PWH, higher CSF suPAR levels correlated with higher CSAR values (r = 0.47, P

BackgroundCervical cancer is the leading cause of cancer death in Sub-Saharan Africa. The risk of developing cancer is increased for women living with human immunodeficiency virus (HIV) infection. It is unknown which factors predict the initiation of curative chemoradiotherapy (CRT) in resource-limited settings and whether HIV is associated with initiating curative CRT in settings with a high HIV burden.MethodsAll women living with and without HIV infection who were initiating curative and noncurative CRT for locally advanced cervical cancer in Botswana were prospectively enrolled in an observational study. The factors associated with receiving CRT were evaluated in all patients and the subgroup of women living with HIV.ResultsOf 519 enrolled women, 284 (55%) initiated CRT with curative intent. The curative cohort included 200 women (70.4%) who were living with HIV and had a median CD4 count of 484.0 cells/μL (interquartile range, 342.0-611.0 cells/μL). In the noncurative cohort, 157 of 235 women (66.8%) were living with HIV and had a median CD4 count of 476.5 cells/μL (interquartile range, 308.0-649.5 cells/μL). HIV status was not associated with initiating curative CRT (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.58-1.56). The factors associated with receiving curative CRT treatment on multivariable analysis in all patients included baseline hemoglobin levels ≥10 g/dL (OR, 1.80; 95% CI, 1.18-2.74) and stage I or II versus stage III or IV disease (OR, 3.16; 95% CI, 2.10-4.75). Women aged >61 years were less likely to receive curative treatment (OR, 0.43; 95% CI, 0.24-0.75). Among women who were living with HIV, higher CD4 cell counts were associated with higher rates of CRT initiation.ConclusionsThe initiation of CRT with curative intent does not depend on HIV status. Significant predictors of CRT initiation include baseline hemoglobin level, disease stage, and age.

Purpose: Botswana has a high prevalence of HIV infection. Currently, there are few data regarding the sociodemographic factors, clinical characteristics, and outcomes of non-Hodgkin lymphoma (NHL)—an AIDS-defining cancer—in the country. Patients and Methods: This study used a prospective cancer registry to identify patients with a new diagnosis of NHL reporting for specialty cancer care at three hospitals in Botswana between October 2010 and August 2016. Treatment patterns and clinical outcomes were analyzed. Results: One hundred four patients with a new diagnosis of NHL were enrolled in this study, 72% of whom had HIV infection. Compared with patients not infected with HIV, patients infected with HIV were younger (median age, 53.9 v 39.1 years; P =.001) and more likely to present with an aggressive subtype of NHL (65.5% v 84.0%; P =.008). All patients infected with HIV received combined antiretroviral therapy throughout the course of the study, and similar chemotherapeutic regimens were recommended for all patients, regardless of subtype or HIV status (six to eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone; or cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab). There was no difference in 1-year mortality among patients not infected with HIV and patients infected with HIV (unadjusted analysis, 52.9% v 37.1%; hazard ratio [HR], 0.73; P =.33; adjusted analysis, HR, 0.57; P =.14). However, when compared with a cohort of patients in the United States matched by subtype, stage, age, sex, and race, patients in Botswana fared worse (1-year mortality, 22.8% v 46.3%; HR, 1.89; P =.001). Conclusion: Among patients with NHL reporting for specialty cancer care in Botswana, there is no association between HIV status and 1-year survival. [ABSTRACT FROM AUTHOR]

Background Cancer is now the leading cause of mortality for persons living with HIV (PLWH) in the United States, but it is uncertain whether PLWH access cancer screening that could lower this burden. We sought to assess cancer screening for breast, cervical, and colon cancer among PLWH compared with the HIV-uninfected population at a multicenter healthcare system over the past two decades. Methods Data were obtained from a prospective, observational HIV clinical care cohort comprised of PLWH engaged in care in the Partners Healthcare System. Patients eligible for cancer screening between the years 2002 and 2016 were included. Patients were matched in a maximum of 1:4 ratio with HIV-uninfected patients from the Massachusetts General Primary Care Practice-Based Research Network based on age, sex, race, year of study entry, and length of follow-up. The mean proportion of time in which eligible patients were guideline concordant for cervical, breast, and colon cancer screening was assessed. Non-parametric tests were used to compared screening rates between PLWH and HIV-infected and on the basis of multiple clinical and sociodemographic factors. Results During the observation period, a total of 495 PLWH were eligible for breast cancer screening, 1011 for cervical cancer screening, and 1965 for colon cancer screening. For each screening group, the majority of PLWH were on antiretroviral therapy (ART) and had relatively high CD4 cell counts (Table 1). Screening rates for PLWH compared with controls were 67.3% vs. 82.8% (P < 0.0001) for breast cancer, 49.0% vs. 73.3% (P < 0.0001) for cervical cancer, and 92.7% vs. 91.2% (P = 0.96) for colon cancer (Figure 1). Among PLWH, factors significantly associated with lower rates of screening guideline concordance were older age, lower CD4 count, HIV-1 RNA >1000 copies/mL, and HIV duration < 5 years for breast cancer, and older age, white race, English language, and lack of ART use for cervical cancer. Conclusion Among patients engaged in longitudinal care, PLWH had significantly lower rates of screening for breast and cervical cancer than HIV-uninfected. Disparity is not explained by racial or primary language differences. Further work to improve access to cancer screening for PLWH is needed. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Despite the rising burden of noncommunicable diseases, access to quality decentralized noncommunicable disease services remain limited in many low- and middle-income countries. Here we describe the strategies we employed to drive the process from adaptation to national endorsement and implementation of the 2016 Botswana primary healthcare guidelines for adults. The strategies included detailed multilevel assessment with broad stakeholder inputs and in-depth analysis of local data; leveraging academic partnerships; facilitating development of supporting policy instruments; and embedding noncommunicable disease guidelines within broader primary health-care guidelines in keeping with the health ministry strategic direction. At facility level, strategies included developing a multimethod training programme for health-care providers, leveraging on the experience of provision of human immunodeficiency virus care and engaging health-care implementers early in the process. Through the strategies employed, the country's first national primary health-care guidelines were endorsed in 2016 and a phased three-year implementation started in August 2017. In addition, provision of primary health-care delivery of noncommunicable disease services was included in the country's 11th national development plan (2017-2023). During the guideline development process, we learnt that strong interdisciplinary skills in communication, organization, coalition building and systems thinking, and technical grasp of best-practices in low- and middle-income countries were important. Furthermore, misaligned agendas of stakeholders, exaggerated by a siloed approach to guideline development, underestimation of the importance of having policy instruments in place and coordination of the processes initially being led outside the health ministry caused delays. Our experience is relevant to other countries interested in developing and implementing guidelines for evidence-based noncommunicable disease services. [ABSTRACT FROM AUTHOR]