Charles Lacey

Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial

Summary Background Randomised placebo-controlled trials have shown that daily oral pre-exposure prophylaxis (PrEP) with tenofovir–emtricitabine reduces the risk of HIV infection. However, this benefit could be counteracted by risk compensation in users of PrEP. We did the PROUD study to assess this effect. Methods PROUD is an open-label randomised trial done at 13 sexual health clinics in England. We enrolled HIV-negative gay and other men who have sex with men who had had anal intercourse without a condom in the previous 90 days. Participants were randomly assigned (1:1) to receive daily combined tenofovir disoproxil fumarate (245 mg) and emtricitabine (200 mg) either immediately or after a deferral period of 1 year. Randomisation was done via web-based access to a central computer-generated list with variable block sizes (stratified by clinical site). Follow-up was quarterly. The primary outcomes for the pilot phase were time to accrue 500 participants and retention; secondary outcomes included incident HIV infection during the deferral period, safety, adherence, and risk compensation. The trial is registered with ISRCTN (number ISRCTN94465371) and ClinicalTrials.gov (NCT02065986). Findings We enrolled 544 participants (275 in the immediate group, 269 in the deferred group) between Nov 29, 2012, and April 30, 2014. Based on early evidence of effectiveness, the trial steering committee recommended on Oct 13, 2014, that all deferred participants be offered PrEP. Follow-up for HIV incidence was complete for 243 (94%) of 259 patient-years in the immediate group versus 222 (90%) of 245 patient-years in the deferred group. Three HIV infections occurred in the immediate group (1·2/100 person-years) versus 20 in the deferred group (9·0/100 person-years) despite 174 prescriptions of post-exposure prophylaxis in the deferred group (relative reduction 86%, 90% CI 64–96, p=0·0001; absolute difference 7·8/100 person-years, 90% CI 4·3–11·3). 13 men (90% CI 9–23) in a similar population would need access to 1 year of PrEP to avert one HIV infection. We recorded no serious adverse drug reactions; 28 adverse events, most commonly nausea, headache, and arthralgia, resulted in interruption of PrEp. We detected no difference in the occurrence of sexually transmitted infections, including rectal gonorrhoea and chlamydia, between groups, despite a suggestion of risk compensation among some PrEP recipients. Interpretation In this high incidence population, daily tenofovir–emtricitabine conferred even higher protection against HIV than in placebo-controlled trials, refuting concerns that effectiveness would be less in a real-world setting. There was no evidence of an increase in other sexually transmitted infections. Our findings strongly support the addition of PrEP to the standard of prevention for men who have sex with men at risk of HIV infection. Funding MRC Clinical Trials Unit at UCL, Public Health England, and Gilead Sciences.

PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial

Summary Background Innovative prevention strategies for HIV-1 transmission are urgently needed. PRO2000 vaginal gel was efficacious against HIV-1 transmission in studies in macaques; we aimed to assess efficacy and safety of 2% and 0·5% PRO2000 gels against vaginal HIV-1 transmission in women in sub-Saharan Africa. Methods Microbicides Development Programme 301 was a phase 3, randomised, double-blind, parallel-group trial, undertaken at 13 clinics in South Africa, Tanzania, Uganda, and Zambia. We randomly assigned sexually active women, aged 18 years or older (≥16 years in Tanzania and Uganda) without HIV-1 infection in a 1:1:1 ratio to 2% PRO2000, 0·5% PRO2000, or placebo gel groups for 52 weeks (up to 104 weeks in Uganda). Randomisation was done by computerised random number generator. Investigators and participants were masked to group assignment. The primary efficacy outcome was incidence of HIV-1 infection before week 52, which was censored for pregnancy and excluded participants without HIV-1 follow-up data or with HIV-1 infection at enrolment. HIV-1 status was established by rapid tests or ELISA at screening at 12 weeks, 24 weeks, 40 weeks, and 52 weeks, and confirmed in a central reference laboratory. The primary safety endpoint was an adverse event of grade 3 or worse. Use of 2% PRO2000 gel was discontinued on Feb 14, 2008, on the recommendation of the Independent Data Monitoring Committee because of low probability of benefit. This trial is registered at http://isrctn.org, number ISRCTN 64716212. Findings We enrolled 9385 of 15 818 women screened. 2591 (95%) of 2734 participants enrolled to the 2% PRO2000 group, 3156 (95%) of 3326 in the 0·5% PRO2000 group, and 3112 (94%) of 3325 in the placebo group were included in the primary efficacy analysis. Mean reported gel use at last sex act was 89% (95% CI 86–91). HIV-1 incidence was much the same between groups at study end (incidence per 100 woman-years was 4·5 [95% CI 3·8–5·4] for 0·5% PRO2000 vs 4·3 [3·6–5·2] for placebo, hazard ratio 1·05 [0·82–1·34], p=0·71), and at discontinuation (4·7 [3·8–5·8] for 2% PRO2000 gel, 3·9 [3·0–4·9] for 0·5% PRO2000 gel, and 3·9 [3·1–5·0] for placebo gel). Incidence of the primary safety endpoint at study end was 4·6 per 100 woman-years (95% CI 3·9–5·4) in the 0·5% PRO2000 group and 3·9 (3·2–4·6) in the placebo group; and was 4·5 (3·7–5·5) in the 2% PRO2000 group at discontinuation. Interpretation Although safe, 0·5% PRO2000 and 2% PRO2000 are not efficacious against vaginal HIV-1 transmission and are not indicated for this use. Funding UK Department for International Development, UK Medical Research Council, European and Developing Countries Clinical Trials Partnership, International Partnership for Microbicides, and Endo Pharmaceuticals Solutions.

Prospects for Control of Herpes Simplex Virus Disease through Immunization

Herpes simplex viruses (HSVs) can cause a variety of infections, including genital herpes. Despite effective antiviral therapy, HSV infections remain a significant worldwide public health problem. Vaccines offer the best hope for controlling spread and limiting HSV disease. This article discusses the pathogenesis and immunobiology of mucocutaneous HSV infections, summarizes the spectrum of diseases caused by HSV, and provides a review of the field of HSV vaccine research. This article also discusses what might be realistically expected of a vaccine intended for control of genital herpes and explores the question of whether a vaccine that is effective in controlling genital HSV disease might also be effective in controlling nongenital HSV disease. The efficacy of such vaccines for the full spectrum of HSV disease will eventually determine the timing and targeting of immunization, ranging from selective immunization in preadolescence to universal childhood immunization as part of the routine childhood regimen.

EUROGIN 2011 roadmap on prevention and treatment of HPV-related disease

The EUROGIN 2011 roadmap reviews the current burden of human papillomavirus (HPV)‐related morbidity, as well as the evidence and potential practice recommendations regarding primary and secondary prevention and treatment of cancers and other disease associated with HPV infection. HPV infection causes ∼600,000 cases of cancer of the cervix, vulva, vagina, anus and oropharynx annually, as well as benign diseases such as genital warts and recurrent respiratory papillomatosis. Whereas the incidence of cervical cancer has been decreasing over recent decades, the incidence of anal and oropharyngeal carcinoma, for which there are no effective screening programs, has been rising over the last couple of decades. Randomized trials have demonstrated improved efficacy of HPV‐based compared to cytology‐based cervical cancer screening. Defining the best algorithms to triage HPV‐positive women, age ranges and screening intervals are priorities for pooled analyses and further research, whereas feasibility questions can be addressed through screening programs. HPV vaccination will reduce the burden of cervical precancer and probably also of invasive cervical and other HPV‐related disease in women. Recent trials demonstrated that prophylactic vaccination also protects against anogenital HPV infection, anogenital intraepithelial lesions and warts associated with vaccine types, in males; and anal HPV infection and anal intraepithelial neoplasia in MSM. HPV‐related oropharyngeal cancer could be treated less aggressively because of better survival compared to cancers of the oropharynx unrelated to HPV. Key findings in the field of cervical cancer prevention should now be translated in cost‐effective strategies, following an organized approach integrating primary and secondary prevention, according to scientific evidence but adapted to the local situation with particular attention to regions with the highest burden of disease.

Phase IIa Safety and Immunogenicity of a Therapeutic Vaccine, TA-GW, in Persons with Genital Warts

A fusion protein vaccine consisting of human papillomavirus 6 L2E7 with Alhydrogel was developed for the treatment of genital warts. Twenty-seven subjects with genital warts received 3 immunizations over 4 weeks in an open-label study. The vaccine was well-tolerated, and all subjects made serum IgG antibodies, predominantly IgG1, against L2E7. Nineteen of 25 tested persons made antigen-specific T cell proliferative responses to L2E7, and peripheral blood mononuclear cells when cultured with L2E7 in vitro produced both interferon-gamma and interleukin (IL)-5, although IL-5 predominated after the final vaccination. Five subjects completely cleared warts within 8 weeks. Subjects whose warts were not cleared by 8 weeks were offered conventional therapy. Recurrence of warts was not seen in any of the 13 persons whose warts cleared by vaccine alone or with conventional therapy. While these preliminary results of the use of this therapeutic immunogen are encouraging, proof of efficacy will require randomized double-blind trials.

Randomized controlled trial of an adjuvanted human papillomavirus (HPV) type 6 L2E7 vaccine: infection of external anogenital warts with multiple HPV types and failure of therapeutic vaccination.

BACKGROUND Cellular immunity is involved in spontaneous clearance of anogenital warts caused, most typically, by human papillomavirus (HPV) type 6 or 11, supporting the concept of therapeutic vaccination. A therapeutic vaccine composed of HPV-6 L2E7 fusion protein and AS02A adjuvant was evaluated in conjunction with conventional therapies in subjects with anogenital warts. METHODS A total of 457 subjects with anogenital warts were screened, of which 320 with HPV-6 and/or HPV-11 infection were enrolled into 2 double-blind, placebo-controlled substudies. Three doses of vaccine or placebo were administered along with either ablative therapy or podophyllotoxin. RESULTS Although a positive trend toward clearance was seen in patients infected with only HPV-6, in neither substudy did the vaccine significantly increase the efficacy of conventional therapies, despite induction of adequate immune responses. Extensive HPV typing by polymerase chain reaction demonstrated that a majority of screened subjects (73.7%) were infected with HPV-6 and/or HPV-11 and that a large proportion (40.1%) were infected with multiple HPV types. HPV types that put subjects at high risk of development of cervical cancer were detected in 39.8% of subjects. CONCLUSIONS Infection with multiple HPV types, including high-risk types, is common in anogenital wart disease. Therapeutic vaccination failed to increase the efficacy of conventional therapies.

British HIV Association, BASHH and FSRH guidelines for the management of the sexual and reproductive health of people living with HIV infection 2008

A Fakoya, H Lamba, N Mackie, R Nandwani, A Brown, EJ Bernard, C Gilling-Smith, C Lacey, L Sherr, P Claydon, S Wallage and B Gazzard British HIV Association (BHIVA), BHIVA Secretariat, Mediscript Ltd, 1 Mountview Court, 310 Friern Barnet Lane, London N20 OLD, British Association for Sexual Health and HIV (BASHH), Royal Society of Medicine, 1 Wimpole Street, London W1G OAE and Faculty of Sexual and Reproductive Health of the Royal College of Obstetricians and Gynaecologists (FSRH), 27 Sussex Place, Regent’s Park, London NW1 4RG, UK

Analysis of the sociodemography of gonorrhoea in Leeds, 1989-93.

Abstract Objective: To investigate the epidemiology of gonorrhoea in an urban area in the United Kingdom. Design: Analysis of all cases of gonorrhoea with regard to age, sex, ethnic group, and socioeconomic group with 1991 census data as a denominator. Setting: Leeds, a comparatively large urban area (population around 700 000) in the United Kingdom. Subjects: All residents of Leeds with culture proved cases of gonorrhoea during 1989-93. Main outcome measure: Relative risk of gonorrhoea. Results: Sex, age, race, and socioeconomic group and area of residence were all independently predictive of risk of infection. Young black men aged 20-29 were at highest risk, with incidences of 3-4% per year. Black subjects were 10 times more likely than white subjects to acquire infection, and subjects from the most deprived socioeconomic areas were more than four times more likely than those from the most affluent areas to acquire infection. Conclusions: Different ethnic and socioeconomic groups vary in their risk of infection with gonorrhoea within an urban area. Targeted interventions and screening to reduce the incidence of sexually transmitted disease are now priorities. Key messages Ethnic group and socioeconomic group or area of residence are independent risk factors for gonorrhoea Ethnic group and factors associated with neighbourhood of residence may modulate sexual risk factors through cultural and behavioural mechanisms Sexual risk reduction and disease screening interventions targeted at groups at greater risk should now be evaluated

Estimation of the impact of genital warts on health-related quality of life

Objectives: One of the two new human papillomavirus (HPV) vaccines protects against HPV types 6 and 11, which cause over 95% of genital warts, in addition to protecting against HPV types 16 and 18. In anticipation of HPV vaccine implementation, the impact of genital warts on health-related quality of life (HRQoL) was measured to assess the potential benefits of the quadrivalent over the bivalent vaccine. Methods: Genitourinary medicine clinic patients aged 18 years and older with a current diagnosis of genital warts were eligible; 81 consented and were interviewed by a member of the research team. A generic HRQoL questionnaire, the EQ-5D (comprising EQ-5D index and EQ visual analogue scale (VAS) scores) and a disease-specific HRQoL instrument, the CECA10, were administered. Previously established UK population norms were used as a control group for EQ-5D comparisons. Results: Cases (with genital warts) had lower EQ VAS and EQ-5D index scores than controls. After adjusting for age a mean difference between cases and controls 30 years of age and under (n  =  70) of 13.9 points (95% CI 9.9 to 17.6, p<0.001) for the EQ VAS and 0.039 points (95% CI 0.005 to 0.068, p = 0.02) on the EQ-5D index (also adjusted for sex) was observed. The difference between cases and controls for the EQ VAS was especially notable in young women. Conclusions: Genital warts are associated with a significant detriment to HRQoL. The potential added benefit of preventing most cases of genital warts by HPV vaccination should be considered in decisions about which HPV vaccine to implement in the United Kingdom.

Randomised controlled trial and economic evaluation of podophyllotoxin solution, podophyllotoxin cream, and podophyllin in the treatment of genital warts

Objectives: To evaluate the efficacy and cost effectiveness of self applied podophyllotoxin 0.5% solution and podophyllotoxin 0.15% cream, compared to clinic applied 25% podophyllin in the treatment of genital warts over 4 weeks. Methods: We conducted a randomised controlled trial in 358 immunocompetent men and women with genital warts of 3 months’ duration or less. Results: In the principal analysis both podophyllotoxin solution (OR 2.93, 95% CI 1.56 to 5.50) and podophyllotoxin cream (OR 1.97, 95% CI 1.04 to 3.70) were associated with significantly increased odds of remission of all warts compared to podophyllin. We performed two further analyses. When subjects defaulting from follow up were assumed to have been cured odds of remission of all warts were also significantly increased both for podophyllotoxin solution (OR 3.04, 95% CI 1.68 to 5.49) and for podophyllotoxin cream (OR 2.46, 95% CI 1.38 to 4.40). When subjects defaulting from follow up were assumed not to have been cured odds of remission of all warts were significantly increased for podophyllotoxin solution (OR 1.92, 95% CI 1.13 to 3.27), but not for podophyllotoxin cream (OR 1.17, 95% CI 0.69 to 2.00). Local side effects were seen in 24% of subjects, and recurrence of warts within 12 weeks of study entry in 43% of all initially cleared subjects, without statistically significant differences between the treatment groups. Direct, indirect, and total costs were similar across the three treatment groups. Podophyllotoxin solution was the most cost effective treatment, followed by podophyllotoxin cream, with podophyllin treatment being the least cost effective. Conclusions: Self treatment of anogenital warts with podophyllotoxin showed greater efficacy and cost effectiveness than clinic based treatment with podophyllin.