Vaccine and Non-Vaccine HPV Types Presence in Adolescents with Vertically Acquired HIV Five Years Post Gardasil Quadrivalent Vaccination: The ZIMGARD Cohort.

BACKGROUND: Human papillomavirus (HPV) vaccination programs are a key intervention in protecting individuals against HPV-related disease. HIV1-infected individuals are at increased risk of HPV-associated cancers. This study was conducted to evaluate the potential role of prophylactic HPV vaccines in preventing new HPV infections among participants with perinatally acquired HIV who received the quadrivalent HPV vaccine at least five years before this study. METHODS: This cross-sectional study was conducted at Newlands Clinic, Harare, Zimbabwe. The clinic provided the Gardasil quadrivalent HPV vaccine (4vHPV) to 624 adolescents living with HIV starting in December 2015. Vaginal and penile swabs were collected and tested for HPV types from the study participants who had received the 4vHPV vaccine 5-6 years before enrolment. RESULTS: We present the results of 98 participants (44.6% female) vaccinated at a median age of 15 years (IQR 12-16). The mean amount of time since vaccination was 6 years (SD: ±0.4). The HPV-positive rate amongst the analyzed swabs was 69% (68/98). Among 30/98 (31%) HPV-positive participants, 13/98 (13%) had low-risk HPV types, and 17/98 (17%) had high-risk HPV types. Twelve participants tested positive for HPV18, only one participant tested positive for HPV16, and an additional four (4.3%) tested positive for either type 6 or 11, with respect to vaccine-preventable low-risk HPV types. CONCLUSION: The Gardasil quadrivalent HPV vaccine (4vHPV) was expected to protect against infection with HPV types 16, 18, 6, and 11. We demonstrated a possible waning of immunity to HPV18 in 17% of the participants, and an associated loss in cross-protection against HPV45. We observed a relatively high prevalence of 'opportunistic non-vaccine HPV types' or 'ecological niche occupiers' in this cohort, and suggest further research on the involvement of these types in cervical and other genital cancers. Our study is one of the few, if not the first, to report on HPV vaccine immunoprotection among people living with HIV (PLWH), thereby setting a baseline for further studies on HPV vaccine effectiveness among PLWH.

Predictors of renal impairment and proteinuria after commencement of antiretroviral therapy in a Zimbabwean HIV cohort.

BACKGROUND: Renal disease prevalence varies widely amongst reported cohorts of people living with HIV (PLWHIV) in sub-Saharan Africa. Renal function testing is not routine in those commencing antiretroviral therapy (ART) in the region, however. Further data on renal disease prevalence and the change associated with ART use are therefore needed. AIM: To explore changes in renal function and associated predictors after 1 year of ART in an adult cohort of PLWHIV from Zimbabwe. METHODS: A retrospective analysis of patients who attended the Newlands Clinic between January 2007 and September 2019. Eligible patients were aged ≥18 years and had measures of serum creatinine at baseline and after 1 year of ART. Predictors of renal function change were assessed by multiple linear regression. RESULTS: 1729 patients were eligible for inclusion. Median age was 36 years (IQR 30-43) and 62.8% were female. After 1 year of ART, the proportion of patients with an estimated glomerular filtration rate (eGFR) <60 ml/min/1.732 did not significantly change (2.0% vs. 1.2%; p = 0.094), but there was a decrease in the proportion of patients with proteinuria (11.0% vs. 5.6%; p < 0.001). Hypertension (B = -6.43; 95% CI -8.97 to -3.89; p < 0.001) and baseline proteinuria (B = -7.33; 95% CI -10.25 to -4.42; p < 0.001) were negative predictors of change in eGFR from baseline, whereas diabetes status was not associated (p = 0.476). CONCLUSION: Proteinuria was common, but its prevalence halved after 1 year of ART. Screening for hypertension could be a simple way to identify patients at risk of renal function decline.

Cervical Cancer Screening Cascade for women living with HIV: a cohort study from Zimbabwe.

Countries with high HIV prevalence, predominantly in sub-Sahahran Africa, have the highest cervical cancer rates globally. HIV care cascades successfully facilitated the scale-up of antiretroviral therapy. A cascade approach could similarly succeed to scale-up cervical cancer screening, supporting WHO's goal to eliminate cervical cancer. We defined a Cervical Cancer Screening Cascade for women living with HIV (WLHIV), evaluating the continuum of cervical cancer screening integrated into an HIV clinic in Zimbabwe. We included WLHIV aged ≥18 years enrolled at Newlands Clinic in Harare from June 2012-2017 and followed them until June 2018. We used a cascade approach to evaluate the full continuum of secondary prevention from screening to treatment of pre-cancer and follow-up. We report percentages, median time to reach cascade stages, and cumulative incidence at two years with 95% confidence intervals (CI). We used univariable Cox proportional hazard regressions to calculate cause-specific hazard ratios with 95% CIs for factors associated with completing the cascade stages. We included 1624 WLHIV in the study. The cumulative incidence of cervical screening was 85.4% (95% CI 83.5-87.1) at two years. Among the 396 WLHIV who received screen-positive tests in the study, the cumulative incidence of treatment after a positive screening test was 79.5% (95% CI 75.1-83.2) at two years. The cumulative incidence of testing negative at re-screening after treatment was 36.1% (95% CI 31.2-40.7) at two years. Using a cascade approach to evaluate the full continuum of cervical cancer screening, we found less-than 80% of WLHIV received treatment after screen-positive tests and less-than 40% were screen-negative at follow-up. Interventions to improve linkage to treatment for screen-positive WLHIV and studies to understand the clinical significance of screen-positive tests at follow-up among WLHIV are needed. These gaps in the continuum of care must be addressed in order to prevent cervical cancer.

Cancer incidence among people living with HIV in Zimbabwe: A record linkage study.

BACKGROUND: People living with HIV (PLWH) are at increased risk of developing cancer. Cancer diagnoses are often incompletely captured at antiretroviral therapy (ART) clinics. AIM: To estimate the incidence and explore risk factors of cancer in a cohort of PLWH in Harare using probabilistic record linkage (PRL). METHODS: We conducted a retrospective cohort study that included PLWH aged ≥16 years starting ART between 2004 and 2017. We used PRL to match records from the Zimbabwe National Cancer Registry (ZNCR) with electronic medical records from an ART clinic in Harare to investigate the incidence of cancer among PLWH initiating ART. We matched records based on demographic data followed by manual clerical review. We followed PLWH up until first cancer diagnosis, death, loss to follow-up, or 31 December 2017, whichever came first. RESULTS: We included 3442 PLWH (64.9% female) with 19 346 person-years (PY) of follow-up. Median CD4 count at ART initiation was 169 cells/mm3 (interquartile range [IQR]: 82-275), median age was 36.6 years (IQR: 30.6-43.4). There were 66 incident cancer cases for an overall incidence rate of 341/100 000 PY (95% confidence interval [CI]: 268-434). Twenty-two of these cases were recorded in the ZNCR only. The most common cancers were cervical cancer (n = 16; 123/100 000 PY; 95% CI: 75-201), Kaposi sarcoma, and lymphoma (both n = 12; 62/100 000 PY; 95% CI: 35-109). Cancer incidence increased with age and decreased with higher CD4 cell counts at ART initiation. CONCLUSION: PRL was key to correct for cancer under-ascertainment in this cohort. The most common cancers were infection-related types, reinforcing the role of early HIV treatment, human papillomavirus vaccination, and cervical cancer screening for cancer prevention in this setting.

Treatment outcomes in HIV infected patients older than 50 years attending an HIV clinic in Harare, Zimbabwe: A cohort study.

There is a growing number of older people living with HIV (OPLHIV). While a significant proportion of this population are adults growing into old age with HIV, there are also new infections among OPLHIV. There is a lack of data describing the outcomes of OPLHIV who commenced antiretroviral therapy (ART) after the age of 50 years in sub-Saharan Africa. We conducted a cohort study of patients who enrolled in care at Newlands Clinic in Harare, Zimbabwe, at ages ≥50 years between February 2004 and March 2020. We examined demographic characteristics, attrition, viral suppression, immunological and clinical outcomes. Specifically, we described prevalent and incident HIV-related communicable and non-communicable comorbidities. We calculated frequencies, medians, interquartile ranges (IQR), and proportions; and used Cox proportional hazards models to identify risk factors associated with death. We included 420 (57% female) who commenced ART and were followed up for a median of 5.6 years (IQR 2.4-9.9). Most of the men were married (n = 152/179, 85%) whereas women were mostly widowed (n = 125/241, 51.9%). Forty per cent (n = 167) had WHO stage 3 or 4 conditions at ART baseline. Hypertension prevalence was 15% (n = 61) at baseline, and a further 27% (n = 112) had incident hypertension during follow-up. During follow-up, 300 (71%) were retained in care, 88 (21%) died, 17 (4%) were lost to follow-up, and 15 (4%) were transferred out. Of those in care, 283 (94%) had viral loads <50 copies/ml, and 10 had viral loads >1000 copies/ml. Seven patients (1.7%) were switched to second line ART during follow-up and none were switched to third-line. Higher baseline CD4 T-cell counts were protective against mortality (p = 0.001) while male sex (aHR: 2.29, 95%CI: 1.21-4.33), being unmarried (aHR: 2.06, 95%CI: 1.13-3.78), and being unemployed (aHR: 2.01, 95%CI: 1.2-3.37) were independent independent risk factors of mortality. There was high retention in care and virologic suppression in this cohort of OPLHIV. Hypertension was a common comorbidity. Being unmarried or unemployed were significant predictors of mortality highlighting the importance of sociologic factors among OPLHIV, while better immune competence at ART commencement was protective against mortality.

Profile of elderly patients receiving antiretroviral therapy at Newlands Clinic in 2020: A cross-sectional study.

BACKGROUND: People living with HIV (PLWH) face new challenges such as accelerated ageing and higher rates of comorbidities including cardiovascular, renal and metabolic diseases as they age. OBJECTIVES: To profile the demographic and clinical characteristics of elderly patients receiving HIV care at Newlands Clinic (NC), Harare, Zimbabwe, as of 01 October 2019. METHODS: A cross-sectional analysis was conducted using clinic data. All patients who were 50 years and older on 01 October 2019 were enrolled. Descriptive statistics (medians, interquartile ranges [IQRs] and proportions) were used to describe patient demographic and clinical characteristics. RESULTS: Out of 6543 patients undergoing care at NC, 1688 (25.8%) were older than 50 years. The median duration of antiretroviral therapy (ART) was 10.9 years (IQR: 7.1-13). Over 90% of all patients had an HIV viral load below 50 copies/mL. Women were more likely than men to be overweight and obese (32% and 25% vs. 18% and 7%, respectively). Hypertension (41.2%), arthritis (19.9%) and chronic kidney disease (11.6%) were common comorbidities differently distributed based on sex. The most common malignancy diagnosed in women was cervical intra-epithelial neoplasia (68% of cancer burden in women) and Kaposi sarcoma was the leading malignancy in men (41% of cancer burden in men). Nearly 20% of patients had at least two chronic non-communicable comorbidities and 5.6% had at least three. CONCLUSION: A high burden of comorbidities was observed amongst HIV-positive elderly patients receiving ART. Age-appropriate monitoring protocols must be developed to ensure optimum quality of care for elderly HIV-positive individuals.

Cervical human papillomavirus prevalence, risk factors and outcomes in a cohort of HIV-infected women in Harare, Zimbabwe.

BACKGROUND: Human papillomavirus (HPV) associated invasive cervical cancer (ICC) is common in Zimbabwe, disproportionately affecting women living with HIV (WLHIV). Understanding high-risk HPV (hrHPV) infection in relation to cervical disease is important for ICC prevention amongst WLHIV. OBJECTIVES: To describe the prevalence of cervical hrHPV, type distribution, associated risk factors and ICC screening outcomes in an urban cohort of Zimbabwean women. METHODS: In this cohort study, WLHIV were tested for hrHPV infection using the Cepheid Xpert® HPV assay and followed up for incident cervical disease. Follow-up assessments were done by visual inspection with acetic acid (VIA). Descriptive statistics and logistic regression were used to describe hrHPV burden and association between hrHPV and potential risk factors. Incidence rates (IR) and rate ratios of cervical disease by hrHPV infection status were also calculated. RESULTS: Amongst 321 WLHIV recruited, hrHPV prevalence was 24.9% (n = 80). Fifty-two of these women (65%) were positive for hrHPV types other than 16 or 18/45. Younger age (22-29 years), early sexual debut (13-16 years) and antiretroviral therapy (ART) regimen (second-line ART) were independently associated with hrHPV positivity. Positive VIA IR ratio between hrHPV-positive and -negative women was 12.57 (95% confidence interval [CI]: 4.14-38.19). Only women with hrHPV infection had incident cervical disease (IR: 6.41/100 person-years, (95% CI: 3.33-12.32). There were no ICC cases by the end of the 2-year follow-up. CONCLUSION: There was a high prevalence of hrHPV infection other than 16 and 18/45 in this cohort. Integrating HPV testing in cervical cancer screening programmes may increase screening intervals in hrHPV-negative women, reducing costs for programmes. We recommend further research into cross protectivity of the bivalent and quadrivalent HPV vaccines against these other hrHPV types.

Mortality trends and causes of death among HIV positive patients at Newlands Clinic in Harare, Zimbabwe.

BACKGROUND: We report trends in mortality patterns and causes among HIV positive patients, who initiated antiretroviral therapy (ART), at an urban clinic in Harare, Zimbabwe. METHODS: A retrospective cohort study was conducted in which routinely collected data for patients enrolled and followed up between February 2004 and December 2017 were assessed. Patients follow up was from the day of the treatment initiation until exit by death, transfer out or loss to follow up. Two doctors categorized causes of death (COD) as tuberculosis (TB), communicable AIDS, non-communicable diseases (NCDs), malignancies, others and unknown. We used competing risk survival analysis, first to estimate all-causes and cause-specific mortality rates over time, and then to assess risk factors of different causes of death. RESULTS: A total of 4 868 patients were followed up for 27 527 person years (PY). Among the 506 patients who died, COD was unknown for 76 patients (15%) and common COD were TB (n = 71, 14%), Malignancies (n = 54, 10.7%) Meningitis (n = 39, 7.7%) and NCDs (n = 60, 11.9%). 49.4% of the deaths were within the first year of starting ART. Median age at death was 36 years (IQR:19-46). There was a near threefold increase in proportion of deaths due to NCDs and malignancies over the period of follow up. Low baseline CD4 cell count and WHO stages 3 & 4 were significant risk factors for all-cause mortality. CONCLUSIONS: TB remains the leading cause of death among HIV infected people. Deaths due to NCDs and malignancies increased over time. ART facilities need to incorporate management of NCDs including cancer as part of comprehensive care of PLHIV to reduce mortality.

Zimbabwe's national third-line antiretroviral therapy program: Cohort description and treatment outcomes.

BACKGROUND: In 2015, Zimbabwe introduced third-line antiretroviral therapy (ART) through four designated treatment centers; three government clinics in Harare and Bulawayo, and Newlands Clinic (NC), operated by a private voluntary organization in Harare. We describe characteristics of patients receiving third line ART and analyzed treatment outcomes in this national programme as of 31 December 2018. METHODS: We described the population using proportions for categorical variables, and medians and interquartile ranges for continuous variables. Patients from NC, where data were more complete, were followed from the date of starting third-line ART until death, transfer, loss to follow up or 31 December 2018. RESULTS: A total of 209 patients had ever received third-line ART: 124 at NC and 85 from the three government clinics. HIV genotype results were available for 89 (72%) patients at NC and fourteen (16.5%) patients in the government clinics. Median duration of third line ART (years) in the government clinics was 2.3 (IQR:0.6-3.4), 1.3 (IQR: 0.7-1.7) and 1 (0.6-1.9). Of the 67 patients who received third line ART in the government clinics for at least six months, 53 (79%) had most recent viral load (VL) < 1000 copies/ml. Data on other treatment outcomes from government clinics were incomplete. From NC: a total of 109 (88%) patients were still in care, 13 (10.5%) had died and 2 (1.5%) were transferred. Median duration of third-line ART was 1.4 years (IQR: 0.6-2.8). Among the 111 NC patients who had received third-line ART for at least 6 months, 83 (75%) had a VL <50 copies/ml and 106 (95.5%) had a VL <1000 copies/ml. CONCLUSION: Our findings demonstrate that, with comprehensive care, patients failing second-line ART can achieve high rates of virological suppression on third-line regimens. There is need to decentralize the provision of third-line ART in Zimbabwe. More needs to be done to improve completeness of data in the government clinics.

Gynecomastia in HIV-positive adult men receiving efavirenz-based antiretroviral therapy at Newlands clinic, Harare, Zimbabwe.

BACKGROUND: Gynecomastia is known to occur in some men taking an efavirenz-based antiretroviral therapy (ART) regimen. However, the incidence and outcomes of gynecomastia are not known in Zimbabwe. We described the characteristics and outcomes of gynecomastia among male patients on an efavirenz-based ART regimen. METHODS: We conducted a retrospective cohort review of data of all male patients aged ≥18 years taking an efavirenz-based regimen at Newlands Clinic, Harare, Zimbabwe before 31 March 2017. The primary outcome was gynecomastia as defined by breast/nipple enlargement reported by patient and confirmed by clinical palpation. Routinely collected data on demographics, baseline CD4, body mass index, duration on efavirenz, clinical presentation and outcomes were extracted from the clinic database and analysed using STATA 12.1. We investigated for any associations with concomitant medicines using cox regression. RESULTS: We analysed data for 1432 men with a median age of 40 years (IQR: 33-48). Half of the patients were in WHO stage 1 at ART commencement. Median body mass index and CD4 count at efavirenz commencement was 21 (IQR: 19-23) and 260 cells/mm3 (IQR: 126-412) respectively. The incidence of gynecomastia was 22/1000 person-years (IQR: 17.3-27.8). Over half of the cases (58%) were bilateral and 75% of all cases developed within two years of starting efavirenz. There were no significant associations with concomitant use of isoniazid (HR: 0.95, p = 0.87) or amlodipine (HR: 0.43, p = 0.24). Gynecomastia resolved in 83.5% of cases following withdrawal of efavirenz with a median time to resolution of 3 months (IQR: 2-9). CONCLUSION: The incidence of gynecomastia among patients taking efavirenz-based ART was low with most cases developing early on during treatment. Most cases resolved completely after withdrawing efavirenz.

Sexually transmitted infections, the silent partner in HIV-infected women in Zimbabwe.

BACKGROUND: Coinfection rates of HIV and sexually transmitted infections (STIs) are not widely reported in Zimbabwe and no local guidelines regarding the screening of STIs in people living with HIV exist. OBJECTIVES: This cross-sectional study was conducted to determine the prevalence and associated risk factors for STI coinfection in a cohort of HIV-infected women. METHODS: Between January and June 2016, 385 HIV-infected women presenting for routine cervical cancer screening were tested for five STIs: Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT), Trichomonas vaginalis (TV), Herpes Simplex Virus (HSV) type 2 and Treponema pallidum (TP). Socio-demographic characteristics and sexual history were recorded. Multiple logistic regression was used to identify factors associated with the diagnosis of non-viral STIs. RESULTS: Two hundred and thirty-three participants (60.5%) had a confirmed positive result for at least one STI: HSV 2 prevalence 52.5%, TV 8.1%, CT 2.1%, NG 1.8% and TP 11.4%. Eighty-seven per cent of the women were asymptomatic for any STI; 62.3% of women with a non-viral STI were asymptomatic. Women who had attended tertiary education were 90% less likely to have a non-viral STI (adjusted odds ratio [aOR]: 0.10, 95% confidence interval [CI]: 0.03-0.39, p < 0.01). Having more than three lifetime sexual partners was a significant predictor for a non-viral STI diagnosis (aOR: 3.3, 95% CI: 1.5-7.2, p < 0.01). CONCLUSION: A high prevalence of predominantly asymptomatic STIs is reported in a cohort of HIV-infected women. Syndromic management results in underdiagnosis of asymptomatic patients. More than three lifetime sexual partners and less formal education are risk factors for coinfection with non-viral STI. High-risk women should be screened using aetiological methods.

HIV drug resistance testing among patients failing second line antiretroviral therapy. Comparison of in-house and commercial sequencing.

INTRODUCTION: HIV genotyping is often unavailable in low and middle-income countries due to infrastructure requirements and cost. We compared genotype resistance testing in patients with virologic failure, by amplification of HIV pol gene, followed by "in-house" sequencing and commercial sequencing. METHODS: Remnant plasma samples from adults and children failing second-line ART were amplified and sequenced using in-house and commercial di-deoxysequencing, and analyzed in Harare, Zimbabwe and at Stanford, U.S.A, respectively. HIV drug resistance mutations were determined using the Stanford HIV drug resistance database. RESULTS: Twenty-six of 28 samples were amplified and 25 were successfully genotyped. Comparison of average percent nucleotide and amino acid identities between 23 pairs sequenced in both laboratories were 99.51 (±0.56) and 99.11 (±0.95), respectively. All pairs clustered together in phylogenetic analysis. Sequencing analysis identified 6/23 pairs with mutation discordances resulting in differences in phenotype, but these did not impact future regimens. CONCLUSIONS: The results demonstrate our ability to produce good quality drug resistance data in-house. Despite discordant mutations in some sequence pairs, the phenotypic predictions were not clinically significant.