Scott Dryden-Peterson

Background: People with human immunodeficiency virus (HIV) (PWH) experience substantially increased risk of anogenital cancer. Whether long-term antiretroviral therapy (ART) reduces anogenital cancer risk is unknown. Methods: A target trial emulation using a case-cohort design among Botswana adults aged 30–65, sampled via a probability-based household survey across 30 communities. Cases of cervical, vulvar, anal, and penile cancer were prospectively ascertained at the country's principal treatment centers. We estimated the marginal relative risk (RR) of incident anogenital cancer by ART duration, compared with adults without HIV, using g-computation from weighted models that accounted for shared determinants of human papillomavirus, and HIV infection, access to cancer care, and ART duration. Results: 14 312 participants were enrolled (42% PWH), including 1045 (79% PWH) with incident anogenital cancer—792 cervical, 106 vulvar, 80 anal, and 67 penile cancers. Compared with people without HIV, the marginal RR (95% CI) of anogenital cancer increased with longer durations of ART (P = .001) (no ART: 4.6; 4.3–5.0; <5 years: 4.0; 3.7–4.3; 5–9 years: 4.6; 4.2–5.0; ≥10 years: 7.4; 6.8–8.1). Individuals receiving ART for ≥10 years had the highest RR for each cancer evaluated: cervix, 4.4 (4.0 to 4.8); vulva, 36 (22–57); anus, 15 (11–20); and penis, 102 (42–250). Prior advanced HIV disease was associated with increased risk but this effect diminished on ART and contributed relatively little to overall risk. Conclusions: Long-term utilization of ART was not associated with a reduction in anogenital cancer risk. Improved prevention strategies are needed for PWH.

Background: Immunocompromised patients remain at risk for protracted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections with persistent viral shedding that could pose a wider public health risk. The optimal therapeutic strategy remains unknown. Methods: We describe a sequential case series of immunocompromised adults with protracted SARS-CoV-2 infection who received dual/extended antiviral therapy (median 23d nirmatrelvir/r; 8d remdesivir). Protracted infection was defined as persistent viral shedding and prolonged symptoms unresponsive to antiviral monotherapy in B-cell-depleted patients. Plasma anti-spike immunoglobulin G (IgG) and spike antigen were analyzed using the single molecule array assay (Simoa), viral RNA levels defined by cycle thresholds (Ct) from clinical assays and quantitative RNA polymerase chain reaction (PCR) testing, and whole virus and targeted nsp5/nsp12 sequencing were performed. Results: Sixteen patients with protracted SARS-CoV-2 infection were treated with dual/extended antivirals. Viral sequencing supported the presence of protracted infections in all tested, but only 1 participant demonstrated mutations conferring antiviral resistance. Humoral immune responses were blunted both at initiation and completion of therapy. All participants responded to dual/extended antiviral therapy with negative PCR at a median of 13 days post-treatment, no evidence of virologic recurrence, and no clinical relapse at 1 year. One patient with recurrent positive SARS-CoV-2 testing was demonstrated to have a new infection by sequencing. Conclusions: Dual/extended antiviral therapy with nirmatrelvir/r and remdesivir can be effective for protracted SARS-CoV-2 infection in B-cell-depleted patients who fail antiviral monotherapy, despite persistently blunted humoral immune responses. Additionally, immunocompromised hosts are at risk of both protracted infection and early re-infection, which can be differentiated by viral sequencing.

Background: The individual risk of severe outcomes following COVID-19 is poorly understood in populations with prior immunity. The lack of contemporary estimates limits support of timely diagnosis and antiviral treatment for individuals most likely to benefit. Objective: To determine the risk of severe outcomes following COVID-19 within strata of comorbidities, including patients without documented infection. Design: Population-based cohort study utilizing electronic medical records and g methods to account for selection bias in the documentation of COVID-19 illnesses. Setting: A large health system in northeastern United States Patients: Adults with increased risk conditions (90% vaccinated) and COVID-19 from June to December 2022. Measurements: Incidence of composite of inpatient admission within 14 days and death within 28 days of COVID-19 diagnosis. Results: An estimated 265,248 patients with at least one increased risk condition developed COVID-19, including 76,996 documented cases. Severe outcomes occurred in 3344 (1.3%) patients following COVID-19— 3147 (1.2%) hospitalizations and 376 (0.14%) deaths. In the absence of treatment, individuals with few increased risk conditions (MASS of 3 or less) accounted for 57% of infections and 0.7% developed severe outcomes. In contrast, 2.3% of patients with multiple increased risk conditions (MASS 4 or greater) or severe immunocompromise experienced severe outcomes, including 81% of deaths. The observed risk reduction with antiviral treatment was -0.1% (-0.2 to 0.02%), -0.6% (-0.9 to -0.4%), -1.3% (-2 to -1%), and -1.9% (-3 to -1%) for patients with MASS 3 or less, MASS 4 and 5, MASS 6 or greater, and severe immunocompromise, respectively. Limitations: Estimated number COVID-19 cases cannot be directly verified Conclusions: Individuals with multiple medical conditions remain at substantial risk for severe outcomes of COVID-19 and benefit from treatment.

PURPOSE: Breast cancer (BC) is the most common female cancer worldwide, and the burden is increasing across sub-Saharan Africa. For women with hormone receptor–positive (HR+) cancers, endocrine therapy (ET) taken for 5-10 years can reduce the risk of recurrence by half. We explored experiences with ET and barriers to utilization among survivors in Botswana. METHODS: We recruited women with nonmetastatic disease from a survivorship cohort who had undergone mastectomy within 1-5 years for semi-structured interviews to explore experiences with treatment. This thematic content analysis focused on ET, so the sample included women with HR+ cancer who should have received ET and HR− women who reported taking ET. RESULTS: We analyzed interviews with 19 women (mean age 54 years, 42% stage I/II, 58% stage III). Three key themes were identified: (1) limited provider counseling, (2) challenges refilling prescriptions at public pharmacies, and (3) high medication and transportation costs associated with private pharmacies. Subthemes included immunohistochemistry result communication, lack of knowledge, frequent public pharmacy stockouts, inconvenient prescription refill policies, and medication switching and discontinuation, especially among participants with low socioeconomic positions (SEPs). Women's persistence, SEP, and financial support facilitated refills. Although some experienced side effects, they were not a common reason for discontinuation. CONCLUSION: BC survivors in Botswana face multilevel barriers to accessing and adhering to ET. Provider and health system improvements are needed to effectively communicate ET importance and increase access to consistently available and affordable medication.

PURPOSE: Women living with HIV (WLWH) experience decreased breast cancer survival. We sought to determine whether WLWH surviving breast cancer also experienced different quality of life (QOL) gain. METHODS: Women who enrolled in the Thabatse Cancer Cohort across oncology centers in Botswana for the initial treatment of stage I-III breast cancer from October 2010 to February 2022 were included. Exclusion criteria were no documented definitive therapy and incomplete data at treatment end or 24 ± 3 months after treatment. QOL was measured quarterly using the SF-8 questionnaire. G methods using weighted exposure and outcome modules were used to mitigate potential bias from imbalances in demographic and cancer characteristics by HIV status. Primary analysis was change in physical component summary (PCS) and mental component summary (MCS) from treatment end to 24 months after treatment for WLWH compared with women without HIV. RESULTS: Of 603 women enrolled, the final analysis included 298, comprising 85 WLWH and 213 women without HIV. Most common reasons for exclusion were no documented definitive treatment (n = 114) and death before 21 months after treatment (n = 137). WLWH were younger, were less wealthy, and had more estrogen receptor/progesterone receptor positive tumors. Overall, PCS and MCS significantly increased from treatment end to 24 months after treatment, from 50.8 to 52.8 and 51.8 to 53.7, respectively. There was no difference in the change of the PCS or MCS with HIV infection, 2.2 (95% CI, –0.4 to 4.9) and 0.6 (95% CI, –1.7 to 2.9), respectively. CONCLUSION: HIV infection did not impede QOL gain at 24 months after treatment in women surviving breast cancer. Further work is needed to clarify the role of HIV on specific treatment-related morbidities and in other malignancies.

The clinical impact of coadministration of the oral SARS-CoV-2 protease inhibitor nirmatrelvir and the pharmacokinetic booster ritonavir among vaccinated populations is uncertain. This study emulat... Visual Nirmatrelvir Plus Ritonavir for Early COVID-19 in a Large U.S. Health System. The clinical impact of coadministration of the oral SARS-CoV-2 protease inhibitor nirmatrelvir and the ... Background: In the EPIC-HR (Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients) trial, nirmatrelvir plus ritonavir led to an 89% reduction in hospitalization or death among unvacc...

Background: In the EPIC-HR trial, nirmatrelvir plus ritonavir led to an 88% reduction in hospitalization or death among unvaccinated outpatients with early COVID-19. Clinical impact of nirmatrelvir plus ritonavir among vaccinated populations is uncertain. Objective: To assess whether nirmatrelvir plus ritonavir reduces risk of hospitalization among outpatients with early COVID-19 in the setting of prevalent SARS-CoV-2 immunity and immune evasive SARS-CoV-2 lineages. Design: Population-based cohort study analyzed to emulate a clinical trial utilizing two-stage, inverse-probability weighted models to account for anticipated bias in testing and treatment. Setting: A large healthcare system providing care for 1.5 million patients in Massachusetts and New Hampshire during Omicron wave (January 1 to May 15, 2022) with staged access and capacity to prescribe nirmatrelvir plus ritonavir. Patients: 30,322 non-hospitalized adults (87.2% vaccinated) aged 50 and older with COVID-19 and without contraindications to nirmatrelvir plus ritonavir. Measurement: Primary outcome was hospitalization within 14 days of COVID-19 diagnosis. Results: During the study period, 6036 (19.9%) patients were prescribed nirmatrelvir plus ritonavir and 24,286 (80.1%) patients were not. Patients prescribed nirmatrelvir were more likely to be older, have more comorbidities, and be unvaccinated. Hospitalization occurred in 40 (0.66%) and 232 (0.96%) patients prescribed and not prescribed nirmatrelvir plus ritonavir, respectively. The adjusted risk ratio was 0.55 (95% confidence interval 0.38 to 0.80, p = 0.002). Observed risk reduction was greater among unvaccinated patients and obese patients. Limitations: Potential for residual confounding due to differential access and uptake of COVID-19 vaccines, diagnostics, and treatment. Conclusions: The overall risk of hospitalization was already low (<1%) following an outpatient diagnosis of COVID-19, but this risk was 45% lower among patients prescribed nirmatrelvir plus ritonavir. Funding: National Institutes of Health (P30 AI060354 and R01 CA236546).

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.

PURPOSE: With intense HIV epidemics, southern African countries have a high burden of classic Hodgkin lymphoma (CHL) and non-Hodgkin lymphoma (NHL). However, suboptimal access to pathology resources limits subtype classification. We sought to assess the diagnostic accuracy of specimens classified as lymphoma and to determine association between discordant pathologic diagnosis and overall survival. METHODS: Seventy patients with CHL or NHL and treated at three Botswana hospitals from 2010 to 2016 were analyzed. Local pathologic assessment relied primarily on morphology. All cases underwent secondary US hematopathology review, which is considered gold standard. RESULTS: The median follow-up was 58 months. The overall reclassification rate was 20 of 70 cases (29%). All 20 CHL cases were correctly classified in Botswana, and mixed cellularity was the most common subtype, diagnosed in 11 (55%) cases. Of 47 confirmed NHL cases, diffuse large B-cell lymphoma was the final US diagnosis in 28 cases (60%), another aggressive B-cell NHL in nine (19%), an indolent B-cell NHL in six (13%), and T-cell NHL in four (9%). Common types of diagnostic discordance included NHL subtype reclassification (11 of 20, 55%) and CHL reclassified as NHL (7 of 20, 35%). Concordant versus discordant diagnosis after secondary review was associated with improved 5-year overall survival (60.1% v 26.3%, P = .0066). Discordant diagnosis was independently associated with increased risk of death (adjusted hazard ratio 2.733; 95% CI, 1.102 to 6.775; P = .0300) even after stratifying results by CHL versus NHL. CONCLUSION: In this single prospective cohort, discordant pathologic diagnosis was associated with a nearly three-fold increased risk of death. Limited access to relatively basic diagnostic techniques impairs treatment decisions and leads to poor patient outcomes in low-resource countries.