GLP-1 agonists for people living with HIV and obesity, is there a potential?

BACKGROUND AND OBJECTIVES: Obesity trends and metabolic dysregulation are rising in people living with HIV using antiretrovirals (ARVs). Underlying causes and preventive strategies are being investigated. Two glucagon like-peptide 1 (GLP-1) agonists, liraglutide and semaglutide, were formerly approved as glucose-lowering drugs and have been recently approved for long-term weight loss in people with obesity. Due to the lack of therapeutic guidelines or clinical trials in people with HIV, we discuss the potential benefits, safety aspects and pharmacological considerations of prescribing liraglutide and semaglutide in people with HIV. RESULTS: Clinical experience is limited to two clinical cases of diabetic people with HIV using liraglutide after which a successful weight loss and glycaemic control were observed. None of the adverse events associated with liraglutide and semaglutide usage indicate an additional risk for people with HIV. Extra caution showed be warranted when initiating GLP-1 agonist therapy in people with HIV taking protease inhibitors who have pre-existing risk factors for heart rate variability to reduce the incidence of RP interval prolongation. GLP-1 agonists are metabolized by endopeptidases, and thus do not generate major drug-drug interactions with most drugs, including ARVs. GLP-s agonists are known to inhibit gastric acid secretion, which warrants caution and close monitoring when combined with atazanavir and oral rilpivirine, two ARVs that require low gastric pH for an optimal absorption. CONCLUSION: Theoretical considerations and a few available clinical observations support semaglutide and liraglutide prescription in people with HIV, with, thus far, no indications of concern regarding efficacy, safety or pharmacological interactions with ARVs.

Screening for intra-anal squamous intra-epithelial lesions in women with a history of human papillomavirus-related vulvar or perianal disease: results of a screening protocol.

AIM: Women with a history of human papillomavirus (HPV)-related cervical, vaginal or vulvar high-grade squamous intra-epithelial lesions (HSILs) or cancer are at increased risk of developing anal squamous intra-epithelial lesions (SILs) or a squamous cell carcinoma of the anus (SCCA). Screening for intra-anal SILs with high-resolution anoscopy (HRA) in high-risk populations is a subject of debate. In this study we aimed to answer the following question: what is the prevalence of intra-anal (H)SIL in women with HPV-related vulvar and/or perianal disease using HRA for screening? METHOD: A retrospective study was performed to evaluate the prevalence of intra-anal (H)SIL in women with a history of vulvar and/or perianal HSIL or (superficially invasive) squamous cell carcinoma (SCC). This study was performed between 2015 and 2018 following implementation of a protocol for intra-anal screening using HRA. RESULTS: Twenty-seven patients, 10 with a history of (superficially invasive) SCC (four vulvar, five perianal, one multizonal) and 17 with HSIL as the worst diagnosis (two perianal, 15 multizonal) were screened for intra-anal lesions using HRA. No anal cancer was found at screening, 6 (22%) patients were diagnosed with intra-anal HSIL and 12 (44%) patients with intra-anal low-grade SIL. CONCLUSIONS: We found a high prevalence of intra-anal HSIL in women previously diagnosed with vulvar and perianal HSIL. Given the clear link between HSIL and SCCA, screening for intra-anal lesions in women with HPV-related genital pathology seems warranted. Future studies should focus on the effect of HSIL treatment on the prevention of anal cancer.

Anal Squamous Intraepithelial Lesions (SILs) in Human Immunodeficiency Virus-Positive Men Who Have Sex With Men: Incidence and Risk Factors of SIL and of Progression and Clearance of Low-Grade SILs.

BACKGROUND: Human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) are at risk of anal squamous cell carcinoma. Data are limited on the natural history of the precursor to this carcinoma, anal squamous intraepithelial lesions (SILs). METHODS: HIV-positive MSM were screened for histopathological SILs by means of high-resolution anoscopy (HRA). For participants without SILs at baseline, we estimated the cumulative incidence and risk factors for SILs. For those with low-grade SILs (LSILs) at baseline, the risk of progression to high-grade SILs (HSILs) and the clearance rate were estimated at the lesion level. RESULTS: Of 807 men without SILs at baseline, 107 underwent follow-up HRA between 1 to 4.5 years later. At the second visit 18 men (16.8%) showed LSIL, and 25 (23.4%) HSIL. Age was associated with incident LSILs (adjusted odds ratio [aOR], 2.10 per 10-year increase in age; P = .01). Of 393 men with LSILs at baseline, 114 underwent follow-up HRA 0.5 to 2.5 years later. Of the 177 LSILs found at baseline, 87 (49.2%) had cleared at the second visit, and 29 (16.4%) had progressed to HSILs. CONCLUSION: Incident LSILs and HSILs were common during follow-up among HIV-positive MSM without dysplasia at baseline. Among men with LSILs at baseline, nearly half of these lesions cleared, and a small portion progressed.

Low- and high-risk human papillomavirus genotype infections in intra-anal warts in HIV-positive men who have sex with men.

BACKGROUND: Anogenital warts are often presumed to represent nondysplastic or low-grade anal intraepithelial neoplasia (LGAIN). We previously demonstrated that up to 20% of intra-anal warts in HIV-positive men who have sex with men (MSM) contain regions of high-grade AIN (HGAIN). OBJECTIVES: To determine the causative human papillomavirus (HPV) types of low- and high- grade dysplastic areas in warts from HIV-positive MSM. METHODS: A total of 42 intra-anal warts from 41 HIV-positive MSM were graded as nondysplastic, LGAIN or HGAIN. Whole-tissue sections (WTS) were analysed with the SPF10 polymerase chain reaction/LiPA25 HPV genotyping system. If the WTS contained multiple HPV types, dysplastic regions were isolated by laser capture microdissection (LCM) for HPV genotyping. RESULTS: Overall, 38 of 42 (91%) WTS tested positive for HPV DNA. Of these, 23 (61%) contained a single HPV type and 15 (39%) contained multiple HPV types. All LCM-selected regions contained no more than one HPV type. Ten of 42 (24%) WTS contained HGAIN disease, of which six (60%) were associated with a high-risk HPV (hrHPV) genotype. Twenty-three of 42 WTS contained LGAIN disease, of which two (9%) were associated with hrHPV. AIN lesions containing hrHPV types were identified using p16 staining. CONCLUSIONS: LGAIN lesions can be caused by high-risk HPV genotypes and vice versa. We therefore recommend routine follow-up and treatment of all dysplastic intra-anal warts for HIV-positive MSM.

The increasing incidence of anal cancer: can it be explained by trends in risk groups?

BACKGROUND: Anal cancer incidence is gradually increasing. The cause of this increase is not exactly known. This systematic literature review aimed to investigate the trend in time of anal cancer incidence and to find an explanation for the supposed increase. METHODS: The TRIP database and PubMed were searched for trends in time in incidence of anal cancer in the general population, for risk factors and risk groups for anal cancer, and for incidence trends in time in these risk groups. RESULTS: Age-adjusted incidence rates have increased in all Western countries during the last decades, up to 2.2% per year. Infection with the oncogenic human papilloma virus is the most important aetiological factor. Besides increasing age, other risk factors have been identified: smoking, sexual practices, in particular receptive anal intercourse, and being human immunodeficiency virus (HIV) positive. The standardised incidence ratio (SIR) is significantly increased in HIV-positive men who have sex with men (MSM) (SIR 77.8), organ transplant recipients (SIR approx. 6) and women with a history of cervical cancer (SIR 6) or cervical intraepithelial neoplasia (SIR 16). Absolute numbers of HIV-positive MSM and organ transplant recipients have increased significantly in the last decades. CONCLUSION: The increasing incidence of anal cancer can be partially explained by an increase in the incidence rate in and absolute number of the most important risk group: HIV-positive MSM. The increasing number of renal transplant recipients probably also contributes. Further studies should answer the question whether these risk groups would benefit from preventive screening for anal cancer.

Topical 5-fluorouracil treatment of anal intraepithelial neoplasia in human immunodeficiency virus-positive men.

BACKGROUND: Anal intraepithelial neoplasia (AIN), a human papillomavirus (HPV)-induced potential precursor lesion of anal cancer, is frequent among human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). So far, only a few prospective studies have been performed on the topical treatment of AIN, especially at the intra-anal location. OBJECTIVES: To evaluate the efficacy and safety of self-administered topical 5-fluorouracil (5-FU) treatment of AIN in HIV-positive MSM. METHODS: High-resolution anoscopy (HRA) was performed and patients with AIN (grade 1-3) were treated with 5-FU twice weekly for a total of 16 weeks. HRA-guided lesional biopsies were repeated after 5-FU treatment for histopathological evaluation. Lesional swabs were obtained before and after treatment for HPV typing and HPV-DNA load determination of the high-risk types HPV16, 18, 31 and 33. Responding patients returned 6 months after treatment for follow-up. RESULTS: A total of 46 patients with AIN were included in this open prospective pilot study; 76% had multifocal disease and 74% had high-grade lesions (AIN 2 or 3). In an intention-to-treat analysis, 26 of 46 patients (57%) responded to 5-FU treatment. Eighteen patients (39%) had a complete clearance of AIN and eight patients (17%) had a partial response. Seventeen patients (37%) did not respond (unchanged grade of AIN in 16 patients and progression from low- to high-grade AIN in one patient). 5-FU treatment led to a significant decrease of HPV16-DNA load and cumulative high-risk HPV-DNA load in both responding and nonresponding patients. Thirty-nine patients (85%) experienced side-effects during therapy, but only two discontinued 5-FU treatment. One patient was lost to follow-up. Six months later, 50% of the complete responders had a recurrence. CONCLUSIONS: A substantial proportion of HIV-positive MSM with AIN completely cleared their lesions with topical 5-FU treatment. In those with partial response, pretreatment with topical 5-FU might facilitate subsequent ablative therapy.

Phase II study of carboplatin and whole body hyperthermia (WBH) in recurrent and metastatic cervical cancer.

OBJECTIVE: Hyperthermia enhances carboplatin cytotoxicity preclinically, and clinical studies have shown radiant heat Whole Body Hyperthermia (WBH) to be safe. In this study, the efficacy and toxicity of the combination of 41.8 degrees C WBH and carboplatin in recurrent and/or metastatic cervical cancer were explored. METHODS: Recurrent and/or metastatic cervical cancer patients were treated with 41.8 degrees C WBH and concurrent carboplatin, cycled every 28 days (max. 6 cycles). RESULTS: Twenty-one of 25 participants were evaluable for response: one complete remission, six partial responses, stable disease in nine patients and progression in five, leading to a response rate of 33%. Three of four evaluable chemotherapy pre-treated patients progressed, while this was seen in only 2 of 17 chemotherapy-naive patients. The median survival is 7.8 months (range 1.3 to 43+) and no patients were lost to follow up. Grades 3/4 toxicities were common: leukopenia in 35%, thrombopenia in 61% and anemia in 22% of all treatments. Excessive, partly reversible renal toxicity was seen in two patients (grades 3 and 4). CONCLUSION: The efficacy of WBH and carboplatin in recurrent and/or metastatic cervical cancer seems comparable to that of other palliative chemotherapy regimens in this disease. The considerable toxicity, though largely manageable, includes unexpected and severe unacceptable renal toxicity. This regimen seems less suitable for palliative care.