Timothy Richard Read

The near disappearance of genital warts in young women 4 years after commencing a national human papillomavirus (HPV) vaccination programme

Background Australia provided free quadrivalent human papillomavirus vaccines to 12–18-year-old girls and women aged ≤26 years from mid-2007 until the end of 2009. After this time, only girls aged 12–13 years had access to free vaccines. Methods Before and after the study, of the proportion of new patients attending Melbourne Sexual Health Centre from mid-2004 to mid-2011, diagnosed with genital warts (GW) by risk group. Results From July 2004 to June 2011, 52 454 new patients were seen at Melbourne Sexual Health Centre and 5021 (9.6%, 95% CI 9.3% to 9.8%) were diagnosed with GW. From July 2004 to June 2007, the proportions with GW either increased or did not change in all groups. Comparing the two 12-month periods of 2007/2008 and 2010/2011, GW declined in women under 21 years from 18.6% to 1.9% and in heterosexual men under 21 years from 22.9% to 2.9%. The ORs per year for diagnosis of GW adjusted for number of sexual partners from July 2007 until June 2011 in women and heterosexual men <21 years were 0.44 (95% CI 0.32 to 0.58) and 0.42 (95% CI 0.31 to 0.60), respectively. There was no significant change in GW in women ≥30 years (OR 0.97, 95% CI 0.84 to 1.12), heterosexual men ≥30 years (OR 0.97, 95% CI 0.89 to 1.06) or in homosexual men (OR 0.95, 95% CI 0.85 to 1.07). Conclusion The dramatic decline and near disappearance of GW in women and men under 21 years of age, 4 years after commencing this programme, suggest that the basic reproductive rate has fallen below one.

Etiologies of nongonococcal urethritis: bacteria, viruses, and the association with orogenital exposure

BACKGROUND The purpose of the present study was to determine pathogens and behaviors associated with nongonococcal urethritis (NGU) and the usefulness of the urethral smear in predicting the presence of pathogens. METHODS We conducted a case-control study of men with and without symptoms of NGU. Sexual practices were measured by questionnaire. First-stream urine was tested for Chlamydia trachomatis, Mycoplasma genitalium, Ureaplasma parvum, U. urealyticum, herpes simplex virus (HSV)-1, HSV-2, adenoviruses, and Gardnerella vaginalis by polymerase chain reaction. RESULTS C. trachomatis (20%), M. genitalium (9%), adenoviruses (4%), and HSV-1 (2%) were more common in cases with NGU (n = 329) after age and sexual risk were adjusted for (P< or =.01); U. urealyticum, U. parvum, and G. vaginalis were not. Infection with adenoviruses or HSV-1 was associated with distinct clinical features, oral sex, and male partners, whereas infection with M. genitalium or C. trachomatis was associated with unprotected vaginal sex. Oral sex was associated with NGU in which no pathogen was detected (P < or = .001). Fewer than 5 polymorphonuclear leukocytes (PMNLs) per high-power field (HPF) on urethral smear were present in 32%, 37%, 38%, and 44% of cases with C. trachomatis, M. genitalium, adenoviruses, and HSV, respectively. CONCLUSION We identified adenoviruses and HSV-1 as significant causes of NGU with distinct clinical and behavioral characteristics and highlighted the association between insertive oral sex and NGU. A urethral PMNL count of > or =5 PMNLs/HPF is not sufficiently sensitive to exclude pathogens in men with urethral symptoms.

Smoking-related health risks among persons with HIV in the strategies for management of antiretroviral therapy clinical trial

OBJECTIVES We sought to determine smoking-related hazard ratios (HRs) and population-attributable risk percentage (PAR%) for serious clinical events and death among HIV-positive persons, whose smoking prevalence is higher than in the general population. METHODS For 5472 HIV-infected persons enrolled from 33 countries in the Strategies for Management of Antiretroviral Therapy clinical trial, we evaluated the relationship between baseline smoking status and development of AIDS-related or serious non-AIDS events and overall mortality. RESULTS Among all participants, 40.5% were current smokers and 24.8% were former smokers. Adjusted HRs were higher for current than for never smokers for overall mortality (2.4; P < .001), major cardiovascular disease (2.0; P = .002), non-AIDS cancer (1.8; P = .008), and bacterial pneumonia (2.3; P < .001). Adjusted HRs also were significantly higher for these outcomes among current than among former smokers. The PAR% for current versus former and never smokers combined was 24.3% for overall mortality, 25.3% for major cardiovascular disease, 30.6% for non-AIDS cancer, and 25.4% for bacterial pneumonia. CONCLUSIONS Smoking contributes to substantial morbidity and mortality in this HIV-infected population. Providers should routinely integrate smoking cessation programs into HIV health care.

Azithromycin failure in Mycoplasma genitalium urethritis.

We report significant failure rates (28%, 95% confidence interval 15%–45%) after administering 1 g azithromycin to men with Mycoplasma genitalium–positive nongonococcal urethritis. In vitro evidence supported reduced susceptibility of M. genitalium to macrolides. Moxifloxacin administration resulted in rapid symptom resolution and eradication of infection in all cases. These findings have implications for management of urethritis.

Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): A randomised, double-blind, placebo-controlled, non-inferiority trial

Background: The optimum dose of key antiretroviral drugs is often overlooked during product development. The ENCORE1 study compared the efficacy and safety of reduced dose efavirenz with standard dose efavirenz in combination with tenofovir and emtricitabine as first-line treatment for HIV infection. An effective and safe reduced dose could yield meaningful cost savings. Methods: ENCORE1 is a continuing non-inferiority trial in HIV-1-infected antiretroviral-naive adults in 38 clinical sites in 13 countries. Participants (plasma HIV-RNA >1000 log copies per mL, CD4 T-cell count 50-500 cells per μL) were randomly assigned by a computer-generated sequence with a blocking factor of four (stratified by clinical site and by screening viral load) to receive tenofovir plus emtricitabine with either a reduced daily dose (400 mg) or a standard dose (600 mg) of efavirenz. Participants, physicians, and all other trial staffwere masked to treatment group. The primary endpoint was the difference in proportions of participants with plasma HIV-RNA of less than 200 copies per mL at 48 weeks. Treatment groups were regarded as non-inferior if the lower limit of the 95% CI for the difference in viral load was less than-10% by modified intention-to-treat analysis. Adverse events were summarised by treatment. This trial is registered with ClinicalTrials.gov, number NCT01011413. Findings: The modified intention-to-treat analysis consisted of 630 patients (efavirenz 400=321; efavirenz 600=309). 32% were women; 37% were African, 33% were Asian, and 30% were white. The mean baseline CD4 cell count was 273 cells per μL (SD 99) and median plasma HIV-RNA was 4.75 log copies per mL (IQR 0.88). The proportion of participants with a viral load below 200 copies per mL at week 48 was 94.1% for efavirenz 400 mg and 92.2% for 600 mg (difference 1.85%, 95% CI-2.1 to 5.79). CD4 T-cell counts at week 48 were significantly higher for the 400 mg group than for the 600 mg group (mean difference 25 cells per μL, 95% CI 6-44; p=0.01). We recorded no difference in grade or number of patients reporting adverse events (efavirenz 400=89.1%, efavirenz 600=88.4%; difference 0.75%, 95% CI-4.19 to 5.69; p=0.77). Study drug-related adverse events were significantly more frequent in the 600 mg group than in the 400 mg group (146% [47] vs 118 [37]), difference-10.5%, 95% CI-18.2 to-2.8; p=0.01) and significantly fewer patients with these events stopped treatment (400 mg=6 [2%], 600 mg=18 [6%], difference-3.96%, 95% CI-6.96 to -0.95; p=0.01). Interpretation: Our findings suggest that a reduced dose of 400 mg efavirenz is non-inferior to the standard dose of 600 mg, when combined with tenofovir and emtricitabine during 48 weeks in ART-naive adults with HIV-1 infection. Adverse events related to the study drug were more frequent with 600 mg efavirenz than with 400 mg. Lower dose efavirenz should be recommended as part of routine care.BACKGROUND The optimum dose of key antiretroviral drugs is often overlooked during product development. The ENCORE1 study compared the efficacy and safety of reduced dose efavirenz with standard dose efavirenz in combination with tenofovir and emtricitabine as first-line treatment for HIV infection. An effective and safe reduced dose could yield meaningful cost savings. METHODS ENCORE1 is a continuing non-inferiority trial in HIV-1-infected antiretroviral-naive adults in 38 clinical sites in 13 countries. Participants (plasma HIV-RNA >1000 log10 copies per mL, CD4 T-cell count 50-500 cells per μL) were randomly assigned by a computer-generated sequence with a blocking factor of four (stratified by clinical site and by screening viral load) to receive tenofovir plus emtricitabine with either a reduced daily dose (400 mg) or a standard dose (600 mg) of efavirenz. Participants, physicians, and all other trial staff were masked to treatment group. The primary endpoint was the difference in proportions of participants with plasma HIV-RNA of less than 200 copies per mL at 48 weeks. Treatment groups were regarded as non-inferior if the lower limit of the 95% CI for the difference in viral load was less than -10% by modified intention-to-treat analysis. Adverse events were summarised by treatment. This trial is registered with ClinicalTrials.gov, number NCT01011413. FINDINGS The modified intention-to-treat analysis consisted of 630 patients (efavirenz 400=321; efavirenz 600=309). 32% were women; 37% were African, 33% were Asian, and 30% were white. The mean baseline CD4 cell count was 273 cells per μL (SD 99) and median plasma HIV-RNA was 4·75 log10 copies per mL (IQR 0·88). The proportion of participants with a viral load below 200 copies per mL at week 48 was 94·1% for efavirenz 400 mg and 92·2% for 600 mg (difference 1·85%, 95% CI -2·1 to 5·79). CD4 T-cell counts at week 48 were significantly higher for the 400 mg group than for the 600 mg group (mean difference 25 cells per μL, 95% CI 6-44; p=0·01). We recorded no difference in grade or number of patients reporting adverse events (efavirenz 400=89·1%, efavirenz 600=88·4%; difference 0·75%, 95% CI -4·19 to 5·69; p=0·77). Study drug-related adverse events were significantly more frequent in the 600 mg group than in the 400 mg group (146% [47] vs 118 [37]), difference -10·5%, 95% CI -18·2 to -2·8; p=0·01) and significantly fewer patients with these events stopped treatment (400 mg=6 [2%], 600 mg=18 [6%], difference -3·96%, 95% CI -6·96 to -0·95; p=0·01). INTERPRETATION Our findings suggest that a reduced dose of 400 mg efavirenz is non-inferior to the standard dose of 600 mg, when combined with tenofovir and emtricitabine during 48 weeks in ART-naive adults with HIV-1 infection. Adverse events related to the study drug were more frequent with 600 mg efavirenz than with 400 mg. Lower dose efavirenz should be recommended as part of routine care. FUNDING Bill & Melinda Gates Foundation, University of New South Wales.

Decline in in-patient treatments of genital warts among young Australians following the national HPV vaccination program

BackgroundThere has been a rapid decline in the number of young heterosexuals diagnosed with genital warts at outpatient sexual health services since the national human papillomavirus (HPV) vaccination program started in Australia in 2007. We assessed the impact of the vaccination program on the number of in-patient treatments for genital warts.MethodsData on in-patient treatments of genital warts in all private hospitals were extracted from the Medicare website. Medicare is the universal health insurance scheme of Australia. In the vaccine period (2007–2011) and pre-vaccine period (2000–2007) we calculated the percentage change in treatment numbers and trends in annual treatment rates in private hospitals. Australian population data were used to calculate rates. Summary rate ratios of average annual trends were determined.ResultsBetween 2000 and 2011, 6,014 women and 936 men aged 15–44 years underwent in-patient treatment for genital warts in private hospitals. In 15–24 year old women, there was a significant decreasing trend in annual treatment rates of vulval/vaginal warts in the vaccine period (overall decrease of 85.3% in treatment numbers from 2007 to 2011) compared to no significant trend in the pre-vaccine period (summary rate ratio (SRR) = 0.33, p < 0.001). In 25–34 year old women, declining trends were seen in both vaccine and pre-vaccine periods (overall decrease of 33% vs. 24.3%), but the rate of change was greater in the vaccine period (SRR = 0.60, p < 0.001). In 35–44 year old women, there was no significant change in both periods (SRR = 0.91, p = 0.14). In 15–24 year old men, there was a significant decreasing trend in annual treatment rates of penile warts in the vaccine period (decrease of 70.6%) compared to an increasing trend in the pre-vaccine period (SRR = 0.76, p = 0.02). In 25–34 year old men there was a significant decreasing trend in the vaccine period compared to no change in the pre-vaccine period (SRR = 0.81, p = 0.04) and in 35–44 year old men there was no significant change in rates of penile warts both periods, but the rate of change was greater in the vaccine period (SRR = 0.70, p = 0.02).ConclusionsThe marked decline in in-patient treatment of vulval/vaginal warts in the youngest women is probably attributable to the HPV vaccine program. The moderate decline in in-patient treatments for penile warts in men probably reflects herd immunity.

Ongoing decline in genital warts among young heterosexuals 7 years after the Australian human papillomavirus (HPV) vaccination programme

Background Australia has provided free quadrivalent human papillomavirus (HPV) vaccines to school girls since mid-2007 and a catch-up programme in the community to women aged up to 26 years in 2007–2009. We describe the temporal trend of genital warts in different populations in Melbourne. Methods We analysed the proportion diagnosed with genital warts for all new patients attending Melbourne Sexual Health Centre from July 2004 to June 2014, stratified by different risk groups and age. Adjusted ORs were calculated to compare the annual trend in the proportion of patients with genital warts in different risk groups in the prevaccination period (before June 2007) and the vaccination period (after July 2007). Results The proportion with genital warts decreased in women aged <21 years, from 18.4% in 2004/2005 to 1.1% in 2013/2014 (p<0.001), but increased in women aged >32 years, from 4.0% to 8.5% (p=0.037). The odds per year for diagnosis of genital warts adjusted for number of sexual partners in the vaccination period were 0.55 (95% CI 0.47 to 0.65) and 0.63 (95% CI 0.54 to 0.74) in women and heterosexual men aged <21 years, respectively. There was no change in adjusted odds of genital warts in both women and men aged >32 years. A small annual decline in genital warts was observed in men who have sex with men (aOR=0.92; 95% CI 0.88 to 0.97). Conclusions Genital warts have now become rare in young Australian women and heterosexual men 7 years after the launch of the national HPV vaccination programme but in stark contrast, remain common in men who have sex with men.

Substantial increases in chlamydia and gonorrhea positivity unexplained by changes in individual-level sexual behaviors among men who have sex with men in an australian sexual health service from 2007 to 2013

Background To determine the risk-adjusted temporal trend of gonorrhea and chlamydia positivity and associated risk behaviors among men who have sex with men (MSM) attending a sexual health clinic in Melbourne in Australia. Methods Gonorrhea and chlamydia positivity by anatomical site adjusted for year of test, age, number of sexual partners, and condom use among MSM attending Melbourne Sexual Health Centre from 2007 to 2013 were calculated using generalized estimating equation regression models. Results A total of 12,873 MSM were included with a median age of 30.0 years. The proportion with pharyngeal, urethral, and anal gonorrhea was 1.7%, 2.3%, and 2.9%, respectively. The adjusted odds of gonorrhea positivity increased by 9% (95% confidence interval [CI], 3%–15%), 11% (95% CI, 6%–17%), and 12% (95% CI, 7%–17%) per year, respectively. The proportion of MSM who were infected with anal chlamydia was 5.6%, with an average increase of 6% (95% CI, 3%–10%) per year; however, no significant change was observed in urethral chlamydia positivity (adjusted odds ratio, 1.02; 95% CI, 0.98–1.06). Increases in gonorrhea and chlamydia positivity were primarily restricted to MSM who reported more than 10 partners in 12 months. The number of partners in the last 12 months fell from 16.6 to 10.5, whereas consistent condom use with casual partners decreased from 64.6% to 58.9% over the study period. Conclusions Gonorrhea and chlamydia have increased among MSM despite the decrease in the number of sexual partners and are occurring primarily in MSM with high numbers of partners and persist after adjusting for known risk factors, suggesting that unmeasured factors (e.g., more assortative mixing patterns) may explain the observed changes.

Factors associated with neurocognitive test performance at baseline: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial

We describe neuropsychological test performance (NP) in antiretroviral treatment (ART)‐naïve HIV‐positive individuals with CD4 cell counts above 500 cells/μL.

The etiology of infectious proctitis in men who have sex with men differs according to HIV status.

We compared the spectrum of pathogens responsible for infectious proctitis between HIV-positive and HIV-negative men who have sex with men. Only 32% of men with herpes simplex virus (HSV)-associated proctitis had visible external anal ulceration.The etiology of infectious proctitis among HIV-positive and HIV-negative men is as follows: chlamydia (23.4% vs. 21.7%, P = 0.7), gonorrhea (13.4% vs. 10.8%, P = 0.5), HSV-1 (14.2% vs. 6.5%, P = 0.04), HSV-2 (22% vs. 12.3%, P = 0.03), lymphogranuloma venereum (7.8% vs. 0.7%, P = 0.004), and multiple infections (17.7% vs. 8.6%, P = 0.017). Thirty-two percent with HSV proctitis had external anal ulceration.