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.

Socioeconomic inequalities in cervical precancer screening among women in Ethiopia, Malawi, Rwanda, Tanzania, Zambia and Zimbabwe: analysis of Population-Based HIV Impact Assessment surveys.

OBJECTIVES: We examined age, residence, education and wealth inequalities and their combinations on cervical precancer screening probabilities for women. We hypothesised that inequalities in screening favoured women who were older, lived in urban areas, were more educated and wealthier. DESIGN: Cross-sectional study using Population-Based HIV Impact Assessment data. SETTING: Ethiopia, Malawi, Rwanda, Tanzania, Zambia and Zimbabwe. Differences in screening rates were analysed using multivariable logistic regressions, controlling for age, residence, education and wealth. Inequalities in screening probability were estimated using marginal effects models. PARTICIPANTS: Women aged 25-49 years, reporting screening. OUTCOME MEASURES: Self-reported screening rates, and their inequalities in percentage points, with differences of 20%+ defined as high inequality, 5%-20% as medium, 0%-5% as low. RESULTS: The sample size of participants ranged from 5882 in Ethiopia to 9186 in Tanzania. The screening rates were low in the surveyed countries, ranging from 3.5% (95% CI 3.1% to 4.0%) in Rwanda to 17.1% (95% CI 15.8% to 18.5%) and 17.4% (95% CI 16.1% to 18.8%) in Zambia and Zimbabwe. Inequalities in screening rates were low based on covariates. Combining the inequalities led to significant inequalities in screening probabilities between women living in rural areas aged 25-34 years, with a primary education level, from the lowest wealth quintile, and women living in urban areas aged 35-49 years, with the highest education level, from the highest wealth quintile, ranging from 4.4% in Rwanda to 44.6% in Zimbabwe. CONCLUSIONS: Cervical precancer screening rates were inequitable and low. No country surveyed achieved one-third of the WHO's target of screening 70% of eligible women by 2030. Combining inequalities led to high inequalities, preventing women who were younger, lived in rural areas, were uneducated, and from the lowest wealth quintile from screening. Governments should include and monitor equity in their cervical precancer screening programmes.

Emergent dolutegravir resistance in integrase-naïve, treatment experienced patients from Zimbabwe.

We report two cases of dolutegravir (DTG) resistance in highly treatment experienced patients. Monitoring for treatment failure and adherence support is important in highly treatment experienced patients taking DTG. What this study adds: Dolutegravir is the mainstay of HIV treatment programmes and emergence of drug resistance to DTG is of public health relevance.

Cutaneous squamous cell carcinoma in vertically acquired HIV and epidermodysplasia verruciformis.

Introduction: Acquired epidermodysplasia verruciformis (EV) is a skin disorder that has been described in individuals with perinatally acquired HIV. Many cases have been identified in sub-Saharan Africa in keeping with the epidemiology of HIV infection compared to the rest of the world, where cases are rare. Epidermodysplasia verruciformis skin lesions may undergo malignant transformation. There are few documented cases of malignant transformation of these skin lesions. We describe a patient with an EV-like skin rash who developed cutaneous squamous cell carcinoma (SCC). Patient presentation: A 25-year-old man, on antiretroviral treatment for 12 years, presented with a generalised skin rash since the age of 11 years, and a 7-month history of a persistent scalp ulcer. He had no history of trauma, radiation or other chronic conditions. Despite an undetectable HIV viral load, he had failed to immune reconstitute (CD4 42 cells/µL). Physical examination revealed a generalised hypopigmented, papular skin rash resembling verruca plana and a 3 cm × 3 cm ulcer with rolled edges on the right parietal region of the scalp. There were no palpable lymph nodes in the head and neck areas. Biopsy of the ulcer revealed moderately differentiated SCC. Management and outcome: Wide local excision of the lesion was done under local anaesthesia and histological analysis confirmed completely excised moderately differentiated SCC. Further examination four weeks later revealed two, smaller, histologically similar scalp lesions which were completely excised. Conclusion: Patients with acquired EV require thorough, frequent examination for skin lesions with possible malignant transformation. Early identification of malignant transformation and treatment with surgical intervention is curative.

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.

Correcting mortality for loss to follow-up: a nomogram applied to antiretroviral treatment programmes in sub-Saharan Africa.

BACKGROUND: The World Health Organization estimates that in sub-Saharan Africa about 4 million HIV-infected patients had started antiretroviral therapy (ART) by the end of 2008. Loss of patients to follow-up and care is an important problem for treatment programmes in this region. As mortality is high in these patients compared to patients remaining in care, ART programmes with high rates of loss to follow-up may substantially underestimate mortality of all patients starting ART. METHODS AND FINDINGS: We developed a nomogram to correct mortality estimates for loss to follow-up, based on the fact that mortality of all patients starting ART in a treatment programme is a weighted average of mortality among patients lost to follow-up and patients remaining in care. The nomogram gives a correction factor based on the percentage of patients lost to follow-up at a given point in time, and the estimated ratio of mortality between patients lost and not lost to follow-up. The mortality observed among patients retained in care is then multiplied by the correction factor to obtain an estimate of programme-level mortality that takes all deaths into account. A web calculator directly calculates the corrected, programme-level mortality with 95% confidence intervals (CIs). We applied the method to 11 ART programmes in sub-Saharan Africa. Patients retained in care had a mortality at 1 year of 1.4% to 12.0%; loss to follow-up ranged from 2.8% to 28.7%; and the correction factor from 1.2 to 8.0. The absolute difference between uncorrected and corrected mortality at 1 year ranged from 1.6% to 9.8%, and was above 5% in four programmes. The largest difference in mortality was in a programme with 28.7% of patients lost to follow-up at 1 year. CONCLUSIONS: The amount of bias in mortality estimates can be large in ART programmes with substantial loss to follow-up. Programmes should routinely report mortality among patients retained in care and the proportion of patients lost. A simple nomogram can then be used to estimate mortality among all patients who started ART, for a range of plausible mortality rates among patients lost to follow-up.

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 of HIV-infected patients starting antiretroviral therapy in sub-Saharan Africa: comparison with HIV-unrelated mortality.

BACKGROUND: Mortality in HIV-infected patients who have access to highly active antiretroviral therapy (ART) has declined in sub-Saharan Africa, but it is unclear how mortality compares to the non-HIV-infected population. We compared mortality rates observed in HIV-1-infected patients starting ART with non-HIV-related background mortality in four countries in sub-Saharan Africa. METHODS AND FINDINGS: Patients enrolled in antiretroviral treatment programmes in Côte d'Ivoire, Malawi, South Africa, and Zimbabwe were included. We calculated excess mortality rates and standardised mortality ratios (SMRs) with 95% confidence intervals (CIs). Expected numbers of deaths were obtained using estimates of age-, sex-, and country-specific, HIV-unrelated, mortality rates from the Global Burden of Disease project. Among 13,249 eligible patients 1,177 deaths were recorded during 14,695 person-years of follow-up. The median age was 34 y, 8,831 (67%) patients were female, and 10,811 of 12,720 patients (85%) with information on clinical stage had advanced disease when starting ART. The excess mortality rate was 17.5 (95% CI 14.5-21.1) per 100 person-years SMR in patients who started ART with a CD4 cell count of less than 25 cells/microl and World Health Organization (WHO) stage III/IV, compared to 1.00 (0.55-1.81) per 100 person-years in patients who started with 200 cells/microl or above with WHO stage I/II. The corresponding SMRs were 47.1 (39.1-56.6) and 3.44 (1.91-6.17). Among patients who started ART with 200 cells/microl or above in WHO stage I/II and survived the first year of ART, the excess mortality rate was 0.27 (0.08-0.94) per 100 person-years and the SMR was 1.14 (0.47-2.77). CONCLUSIONS: Mortality of HIV-infected patients treated with combination ART in sub-Saharan Africa continues to be higher than in the general population, but for some patients excess mortality is moderate and reaches that of the general population in the second year of ART. Much of the excess mortality might be prevented by timely initiation of ART.

A case report of untreatable HIV infection in Harare, Zimbabwe.

INTRODUCTION: Zimbabwe, like other resource limited countries, manages HIV infection using the public health approach with standard antiretroviral therapy (ART) regimens for first, second and third-line treatment. Third-line ART is the last available treatment option and is based on dolutegravir and darunavir use after HIV drug resistance testing. PATIENT PRESENTATION: We report here a 17-year-old patient on dolutegravir (DTG) and Darunavir based third-line antiretroviral therapy (ART) previously exposed to raltegravir who develops multidrug resistance HIV to the four ART classes available in Zimbabwe. MANAGEMENT AND OUTCOME: A trophism assay revealed that patient has CXCR4 trophic virus and hence will not benefit from Maraviroc. Patient is currently stable and receiving a holding regimen of abacavir, lamivudine and lamivudine. CONCLUSION: This is the first documented case of multiclass resistance to the four available ART classes in Zimbabwe. The development and transmission of multiclass HIV drug resistance in resource limited settings has potential to undo the gains of national ART programs. There is need to ensure optimum adherence to ART even in the era of DTG.

Tolerability of Isoniazid Preventive Therapy in an HIV-Infected Cohort of Paediatric and Adolescent Patients on Antiretroviral Therapy from a Resource-Limited Setting: A Retrospective Cohort Study.

BACKGROUND: Treating patients with latent tuberculosis infection (LTBI) to prevent development of active disease is an essential strategy for eliminating TB. There are concerns regarding the use of isoniazid due to the potential for hepatotoxicity. This study was conducted to determine the incidence of adverse hepatic events after isoniazid preventive therapy (IPT) commencement in a cohort of HIV-infected paediatric and adolescent patients on antiretroviral therapy (ART). METHODS: This was a retrospective records review, using data from HIV-infected paediatric and adolescent patients collected during routine clinical visits at Newlands Clinic, Harare, Zimbabwe. Patients included in the analysis had commenced IPT between January 2014 and June 2015 (inclusive) whilst receiving ART. A survival analysis was conducted for the period that participants were receiving IPT with end-points defined by grade 3 or grade 4 elevations in alanine aminotransferase (ALT) levels. RESULTS: Data from 438 patients commenced on IPT were analysed; 202 (46.1%) of them were female. The median age at IPT commencement was 10 (IQR = 7-12) years. Twenty-eight patients developed grade 3 or 4 elevations in ALT. Concomitant use of nevirapine as part of an ART regimen was the only factor that showed a statistically significant association with ALT elevation [relative risk (RR): 2.7; confidence interval (CI): 1.2-6.3, p = 0.012] compared with those not receiving nevirapine. The incidence of grade 3 or 4 elevations in ALT was 31.5/100 person-years (CI 20.9-45.5). CONCLUSION: The incidence of IPT-associated ALT elevations was high in this population. We recommend vigilant monitoring of liver enzymes for patients receiving IPT, especially in patients concomitantly receiving nevirapine.

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.

Tuberculosis after initiation of antiretroviral therapy in low-income and high-income countries.

We examined the incidence of and risk factors for tuberculosis during the first year of highly active antiretroviral therapy in low-income (4540 patients) and high-income (22,217 patients) countries. Although incidence was much higher in low-income countries, the reduction in the incidence of tuberculosis associated with highly active antiretroviral therapy was similar: the rate ratio for months 7-12 versus months 1-3 was 0.48 (95% confidence interval, 0.36-0.64) in low-income countries and 0.36 (95% confidence interval, 0.26-0.50) in high-income countries. A low CD4 cell count at the start of therapy was the most important risk factor in both settings.

Early mortality and loss to follow-up in HIV-infected children starting antiretroviral therapy in Southern Africa.

BACKGROUND: Many HIV-infected children in Southern Africa have been started on antiretroviral therapy (ART), but loss to follow up (LTFU) can be substantial. We analyzed mortality in children retained in care and in all children starting ART, taking LTFU into account. PATIENTS AND METHODS: Children who started ART before the age of 16 years in 10 ART programs in South Africa, Malawi, Mozambique, and Zimbabwe were included. Risk factors for death in the first year of ART were identified in Weibull models. A meta-analytic approach was used to estimate cumulative mortality at 1 year. RESULTS: Eight thousand two hundred twenty-five children (median age 49 months, median CD4 cell percent 11.6%) were included; 391 (4.8%) died and 523 (7.0%) were LTFU in the first year. Mortality at 1 year was 4.5% [95% confidence interval (CI): 2.8% to 7.4%] in children remaining in care, but 8.7% (5.4% to 12.1%) at the program level, after taking mortality in children and LTFU into account. Factors associated with mortality in children remaining in care included age [adjusted hazard ratio (HR) 0.37; 95% CI: 0.25 to 0.54 comparing > or =120 months with <18 months], CD4 cell percent (HR: 0.56; 95% CI: 0.39 to 0.78 comparing > or =20% with <10%), and clinical stage (HR: 0.12; 95% CI: 0.03 to 0.45 comparing World Health Organization stage I with III/IV). CONCLUSIONS: In children starting ART and remaining in care in Southern Africa mortality at 1 year is <5% but almost twice as high at the program level, when taking LTFU into account. Age, CD4 percentage, and clinical stage are important predictors of mortality at the individual level.