Ruanne V. Barnabas

Epidemiology of HPV 16 and cervical cancer in Finland and the potential impact of vaccination: mathematical modelling analyses.

Background Candidate human papillomavirus (HPV) vaccines have demonstrated almost 90%-100% efficacy in preventing persistent, type-specific HPV infection over 18 mo in clinical trials. If these vaccines go on to demonstrate prevention of precancerous lesions in phase III clinical trials, they will be licensed for public use in the near future. How these vaccines will be used in countries with national cervical cancer screening programmes is an important question. Methods and Findings We developed a transmission model of HPV 16 infection and progression to cervical cancer and calibrated it to Finnish HPV 16 seroprevalence over time. The model was used to estimate the transmission probability of the virus, to look at the effect of changes in patterns of sexual behaviour and smoking on age-specific trends in cancer incidence, and to explore the impact of HPV 16 vaccination. We estimated a high per-partnership transmission probability of HPV 16, of 0.6. The modelling analyses showed that changes in sexual behaviour and smoking accounted, in part, for the increase seen in cervical cancer incidence in 35- to 39-y-old women from 1990 to 1999. At both low (10% in opportunistic immunisation) and high (90% in a national immunisation programme) coverage of the adolescent population, vaccinating women and men had little benefit over vaccinating women alone. We estimate that vaccinating 90% of young women before sexual debut has the potential to decrease HPV type-specific (e.g., type 16) cervical cancer incidence by 91%. If older women are more likely to have persistent infections and progress to cancer, then vaccination with a duration of protection of less than 15 y could result in an older susceptible cohort and no decrease in cancer incidence. While vaccination has the potential to significantly reduce type-specific cancer incidence, its combination with screening further improves cancer prevention. Conclusions HPV vaccination has the potential to significantly decrease HPV type-specific cervical cancer incidence. High vaccine coverage of women alone, sustained over many decades, with a long duration of vaccine-conferred protection, would have the greatest impact on type-specific cancer incidence. This level of coverage could be achieved through national coordinated programmes, with surveillance to detect cancers caused by nonvaccine oncogenic HPV types.

Systematic review and meta-analysis of community and facility-based HIV testing to address linkage to care gaps in sub-Saharan Africa

HIV testing and counselling is the first crucial step for linkage to HIV treatment and prevention. However, despite high HIV burden in sub-Saharan Africa, testing coverage is low, particularly among young adults and men. Community-based HIV testing and counselling (testing outside of health facilities) has the potential to reduce coverage gaps, but the relative impact of different modalities is not well assessed. We conducted a systematic review of HIV testing modalities, characterizing community (home, mobile, index, key populations, campaign, workplace and self-testing) and facility approaches by population reached, HIV positivity, CD4 count at diagnosis and linkage. Of 2,520 abstracts screened, 126 met eligibility criteria. Community HIV testing and counselling had high coverage and uptake and identified HIV-positive people at higher CD4 counts than facility testing. Mobile HIV testing reached the highest proportion of men of all modalities examined (50%, 95% confidence interval (CI) = 47–54%) and home with self-testing reached the highest proportion of young adults (66%, 95% CI = 65–67%). Few studies evaluated HIV testing for key populations (commercial sex workers and men who have sex with men), but these interventions yielded high HIV positivity (38%, 95% CI = 19–62%) combined with the highest proportion of first-time testers (78%, 95% CI = 63–88%), indicating service gaps. Community testing with facilitated linkage (for example, counsellor follow-up to support linkage) achieved high linkage to care (95%, 95% CI = 87–98%) and antiretroviral initiation (75%, 95% CI = 68–82%). Expanding home and mobile testing, self-testing and outreach to key populations with facilitated linkage can increase the proportion of men, young adults and high-risk individuals linked to HIV treatment and prevention, and decrease HIV burden.This article has not been written or reviewed by Nature editors. Nature accepts no responsibility for the accuracy of the information provided.

High HIV testing uptake and linkage to care in a novel program of home-based HIV counseling and testing with facilitated referral in KwaZulu-Natal, South Africa.

Objective:For antiretroviral therapy (ART) to have a population-level HIV prevention impact, high levels of HIV testing and effective linkages to HIV care among HIV-infected persons are required. Methods:We piloted home-based counseling and testing (HBCT) with point-of-care CD4 count testing and follow-up visits to facilitate linkage of HIV-infected persons to local HIV clinics and uptake of ART in rural KwaZulu-Natal, South Africa. Lay counselor follow-up visits at months one, three and six evaluated the primary outcome of linkage to care. Plasma viral load was measured at baseline and month six. Results:671 adults were tested for HIV (91% coverage) and 201 (30%) were HIV-infected, of which 73 (36%) were new diagnoses. By month three, 90% of HIV-infected persons not on ART at baseline had visited an HIV clinic and 80% of those eligible for ART at baseline by South African guidelines (CD4⩽200 cells/&mgr;L at the time of the study) had initiated ART. Among HIV-infected participants who were eligible for ART at baseline, mean viral load decreased by 3.23 log10 copies/mL (p<0.001) and the proportion with viral load suppression increased from 20% to 80% between baseline and month six. Conclusions:In this pilot of HBCT and linkages to care in KwaZulu-Natal, 91% of adults were tested for HIV. Linkage to care was ∼90% both among newly-identified HIV-infected persons as well as known HIVinfected persons who were not engaged in care. Among those eligible for ART, a high proportion initiated ART and achieved viral suppression, indicating high adherence and reduced infectiousness.

Strategies for the introduction of human papillomavirus vaccination: modelling the optimum age- and sex-specific pattern of vaccination in Finland

Phase III trials have demonstrated the efficacy of human papillomavirus (HPV) vaccines in preventing transient and persistent high-risk (hr) HPV infection and precancerous lesions. A mathematical model of HPV type 16 infection and progression to cervical cancer, parameterised to represent the infection in Finland, was used to explore the optimal age at vaccination and pattern of vaccine introduction. In the long term, the annual proportion of cervical cancer cases prevented is much higher when early adolescents are targeted. Vaccinating against hr HPV generates greater long-term benefits if vaccine is delivered before the age at first sexual intercourse. However, vaccinating 12 year olds delays the predicted decrease in cervical cancer, compared to vaccinating older adolescents or young adults. Vaccinating males as well as females has more impact on the proportion of cases prevented when vaccinating at younger ages. Implementing catch-up vaccination at the start of a vaccination programme would increase the speed with which a decrease in HPV and cervical cancer incidence is observed.

Adding a quadrivalent human papillomavirus vaccine to the UK cervical cancer screening programme: A cost-effectiveness analysis

BackgroundWe assessed the cost-effectiveness of adding a quadrivalent (6/11/16/18) human papillomavirus (HPV) vaccine to the current screening programme in the UK compared to screening alone.MethodsA Markov model of the natural history of HPV infection incorporating screening and vaccination was developed. A vaccine that prevents 98% of HPV 6, 11, 16 and 18-associated disease, with a lifetime duration and 85% coverage, in conjunction with current screening was considered.ResultsVaccination with screening, compared to screening alone, was associated with an incremental cost-effectiveness ratio of £21,059 per quality adjusted life year (QALY) and £34,687 per life year saved (LYS). More than 400 cases of cervical cancer, 6700 cases of cervical intraepithelial neoplasia and 4750 cases of genital warts could be avoided per 100,000 vaccinated girls. Results were sensitive to assumptions about the need for a booster, the duration of vaccine efficacy and discount rate.ConclusionThese analyses suggest that adding a quadrivalent HPV vaccine to current screening in the UK could be a cost-effective method for further reducing the burden of cervical cancer.

The predicted effect of changes in cervical screening practice in the UK: results from a modelling study.

In 2003, the National Health Service Cervical Screening Programme (NHSCSP) announced that its screening interval would be reduced to 3 years in women aged 25–49 and fixed at 5 years in those aged 50–64, and that women under 25 years will no longer be invited for screening. In order to assess these and possible further changes to cervical screening practice in the UK, we constructed a mathematical model of cervical HPV infection, cervical intraepithelial neoplasia and invasive cervical cancer, and of UK age-specific screening coverage rates, screening intervals and treatment efficacy. The predicted cumulative lifetime incidence of invasive cervical cancer in the UK is 1.70% in the absence of screening and 0.77% with pre-2003 screening practice. A reduction in lifetime incidence to 0.63% is predicted following the implementation of the 2003 NHSCSP recommendations, which represents a 63% reduction compared to incidence rates in the UK population if it were unscreened. The model suggests that, after the implementation of the 2003 recommendations, increasing the sensitivity of the screening test regime from its current average value of 56 to 90% would further reduce the cumulative lifetime incidence of invasive cervical cancer to 0.46%. Alternatively, extending screening to women aged 65–79 years would further reduce the lifetime incidence to 0.56%. Screening women aged 20–25 years would have minimal impact, with the cumulative lifetime incidence decreasing from 0.63 to 0.61%. In conclusion, the study supports the 2003 recommendations for changes to cervical screening intervals.

Persisting with prevention: The importance of adherence for HIV prevention

BackgroundOnly four out of 31 completed randomized controlled trials (RCTs) of HIV prevention strategies against sexual transmission have shown significant efficacy. Poor adherence may have contributed to the lack of effect in some of these trials. In this paper we explore the impact of various levels of adherence on measured efficacy within an RCT.AnalysisWe used simple quantitative methods to illustrate the impact of various levels of adherence on measured efficacy by assuming a uniform population in terms of sexual behavior and the binomial model for the transmission probability per partnership.At 100% adherence the measured efficacy within an RCT is a reasonable approximation of the true biological efficacy. However, as adherence levels fall, the efficacy measured within a trial substantially under-estimates the true biological efficacy. For example, at 60% adherence, the measured efficacy can be less than half of the true biological efficacy.ConclusionPoor adherence during a trial can substantially reduce the power to detect an effect, and improved methods of achieving and maintaining high adherence within trials are needed. There are currently 12 ongoing HIV prevention trials, all but one of which require ongoing user-adherence. Attention must be given to methods of maximizing adherence when piloting and designing RCTs and HIV prevention programmes.

Infectious Co-factors in HIV-1 transmission Herpes Simplex Virus type-2 and HIV-1: New Insights and interventions

Over the last thirty years, epidemiologic and molecular studies indicate a strong and synergist relationship between the dual epidemics of herpes simplex type 2 (HSV-2) and HIV-1 infection. While prospective studies show that HSV-2 infection increases the risk for HIV-1 acquisition by 2- to 3-fold, HSV-2 suppression with standard prophylactic doses of HSV-2 therapy did not prevent HIV-1 acquisition. Reconciling these discrepancies requires understanding recent HSV-2 pathogenesis research, which indicates HSV-2 infection is not a latent infection with infrequent recurrence but a near constant state of reactivation and viral shedding which is not completely suppressed by standard antivirals. Because current antivirals do not prevent or fully suppress HSV-2 replication, priorities are HSV-2 vaccine development and antivirals that reach high concentrations in the genital mucosa and suppress the persistent genital inflammation associated with genital herpes reactivation in order to reduce the increased susceptibility to HIV-1 infection associated with HSV-2. HIV-1 and HSV-2 synergy is also seen among co-infected individuals who exhibit higher HIV-1 viral load compared to HSV-2 uninfected individuals. Standard HSV-2 therapy modestly lowers HIV-1 viral load and is associated with slower HIV-1 disease progression. A promising area of research is higher doses of HSV-2 suppressive therapy achieving a greater reduction in plasma HIV-1 RNA, which could translate to greater reductions in HIV-1 disease progression and infectiousness. However, many questions remain to be answered including potential effectiveness and cost-effectiveness of higher dose HSV-2 suppressive therapy. Mathematical models of HSV-2 and HIV-1 at a population level would be useful tools to estimate the potential impact and cost-effectiveness of higher dose HSV-2 suppressive therapy.

Initiation of antiretroviral therapy and viral suppression after home HIV testing and counselling in KwaZulu-Natal, South Africa, and Mbarara district, Uganda: a prospective, observational intervention study

OBJECTIVE Antiretroviral therapy (ART) significantly decreases HIV-associated morbidity, mortality, and HIV transmission through HIV viral load suppression. In high HIV prevalence settings, outreach strategies are needed to find asymptomatic HIV positive persons, link them to HIV care and ART, and achieve viral suppression. METHODS We conducted a prospective intervention study in two rural communities in KwaZulu-Natal, South Africa, and Mbabara district, Uganda. The intervention included home HIV testing and counseling (HTC), point-of-care CD4 count testing for HIV positive persons, referral to care, and one month then quarterly lay counselor follow-up visits. The outcomes at 12 months were linkage to care, and ART initiation and viral suppression among HIV positive persons eligible for ART (CD4≤350 cells/μL). FINDINGS 3,393 adults were tested for HIV (96% coverage), of whom 635 (19%) were HIV positive. At baseline, 36% of HIV positive persons were newly identified (64% were previously known to be HIV positive) and 40% were taking ART. By month 12, 619 (97%) of HIV positive persons visited an HIV clinic, and of 123 ART eligible participants, 94 (76%) initiated ART by 12 months. Of the 77 participants on ART by month 9, 59 (77%) achieved viral suppression by month 12. Among all HIV positive persons, the proportion with viral suppression (<1,000 copies/mL) increased from 50% to 65% (p=<0.001) at 12 months. INTERPRETATION Community-based HTC in rural South Africa and Uganda achieved high testing coverage and linkage to care. Among those eligible for ART, a high proportion initiated ART and achieved viral suppression, indicating high adherence. Implementation of this HTC approach by existing community health workers in Africa should be evaluated to determine effectiveness and costs.

The role of coinfections in HIV epidemic trajectory and positive prevention: a systematic review and meta-analysis

Objectives:Recurrent or persistent coinfections may increase HIV viral load and, consequently, risk of HIV transmission, thus increasing HIV incidence. We evaluated the association between malaria, herpes simplex virus type 2 (HSV-2) and tuberculosis (TB) coinfections and their treatment on HIV viral load. Design:Systematic review and meta-analysis of the association of malaria, HSV-2 and TB coinfections and their treatment with HIV viral load. Methods:PubMed and Embase databases were searched to 10 February 2010 for studies in adults that reported HIV plasma and/or genital viral load by coinfection status or treatment. Meta-analyses were conducted using random-effects models. Results:Forty-five eligible articles were identified (six malaria, 20 HSV-2 and 19 TB). There was strong evidence of increased HIV viral load with acute malaria [0.67 log10 copies/ml, 95% confidence interval (CI) 0.15–1.19] and decreased viral load following treatment (−0.37 log10 copies/ml, 95% CI −0.70 to −0.04). Similarly, HSV-2 infection was associated with increased HIV viral load (0.18 log10 copies/ml, 95% CI 0.01–0.34), which decreased with HSV suppressive therapy (−0.28 log10 copies/ml, 95% CI −0.36 to −0.19). Active TB was associated with increased HIV viral load (0.40 log10 copies/ml, 95% CI 0.13–0.67), but there was no association between TB treatment and viral load reduction (log10 copies/ml −0.02, 95% CI −0.19 to 0.15). Conclusion:Coinfections may increase HIV viral load in populations where they are prevalent, thereby facilitating HIV transmission. These effects may be reversed with treatment. However, to limit HIV trajectory and optimize positive prevention for HIV-infected individuals pre-antiretroviral therapy, we must better understand the mechanisms responsible for augmented viral load and the magnitude of viral load reduction required, and retune treatment regimens accordingly.