David White

Long-term persistence of primary genotypic resistance after HIV-1 seroconversion

Primary infection with drug-resistant HIV-1 is well documented. We have followed up patients infected with such viruses to determine the stability of resistance-associated mutations. Fourteen patients who experienced primary infection with genotypic evidence of resistance were followed for up to 3 years. Drug resistance-associated mutations persisted over time in most patients studied. In particular, M41L, T69N, K103N, and T215 variants within reverse transcriptase (RT) and multidrug resistance demonstrated little reversion to wild-type virus. By contrast, Y181C and K219Q in RT, occurring alone, disappeared within 25 and 9 months, respectively. Multidrug resistance in 2 patients was found to be stable for up to 18 months, the maximum period studied. We conclude that certain resistance-associated mutations are highly stable and these data support the recommendation that all new HIV diagnoses in areas where primary resistance may occur should undergo genotyping irrespective of whether the date of seroconversion is known.

Concentrations of nevirapine, lamivudine and stavudine in semen of HIV-1-infected men.

ObjectiveTo determine the concentrations of nevirapine (NVP), lamivudine (3TC) and stavudine (D4T) in seminal and blood plasma in HIV-1-infected men. MethodsTwelve HIV-1-infected men on NVP-containing regimens including 3TC (n = 8) or D4T (n = 11) provided 23 blood plasma and 22 seminal plasma samples for drug concentration and viral load quantitation. Concentrations of all drugs were assessed by sensitive validated high performance liquid chromatography (HPLC) assays. Blood plasma and seminal plasma viral loads were measured using nucleic acid sequence-based amplification (NASBA). Samples were grouped according to time after drug ingestion, 0–2, 2–4, 4–8 and 8–12 h. For matched seminal and blood plasma samples, obtained within 1 h of each other, a seminal : blood plasma ratio was calculated. ResultsThe concentration of NVP in seminal plasma appeared to mirror the concentrations in blood plasma. Absolute median seminal plasma NVP concentrations at 0–2, 2–4, 4–8 and 8–12 h were 3.1 μg/ml (range 1.7–4.89), 2.68 μg/ml (2.5–3.9), 2.5 μg/ml (2.3–2.7) and 3.09 μg/ml (1.3–9.1). The median seminal : blood plasma ratios for the four time periods were 0.54 (range 0.34–0.85), 0.83 (range 0.43–1.08), 0.53 (0.48–0.59), and 0.61 (0.59–0.78). 3TC and D4T appeared to reach concentrations in seminal plasma of a similar magnitude or higher than concentrations in blood plasma. The median seminal plasma viral load for all patients was less than 800 copies/ml (range < 800–11 000). The median blood plasma viral load was less than 400 copies/ml (< 400–1100). ConclusionNVP reaches concentrations in the semen approximately 60% of those in the blood plasma throughout the 12 h dosing period. In a smaller dataset, 3TC and D4T concentrations in blood plasma and seminal plasma were similar. These data may well have implications for the evolution of drug-resistant virus within the genital tract.

The costs of treating external genital warts in England and Wales: a treatment pattern analysis

The objective of the study was to determine the cost implications of patterns of treatment for patients with external genital warts. A retrospective case note review was carried out at six genitourinary medicine (GUM) clinics in the UK. Significant variations in the total costs of care were observed across the clinics and across the choice of therapy. The cost per successful outcome was ?221.81 for males and ?211.07 for females. A minority of patients accounted for the majority of costs, for example the 30.1% of male patients who recorded six or more visits contributed 66.2% of the total cost. Costs also varied significantly by therapy sequence chosen. Patients who remained on their initial therapy experienced the lowest costs, with the extent to which patients shifted therapies substantially impacting on costs. Therapy sequences involving podophyllin were found to be the most expensive options in achieving a completed episode of care. We concluded that a high proportion of costs for GUM clinics is due to the failure of the initial therapy and by subsequent therapy switching. A greater emphasis on the selection of alternative treatment options, such as the patient-applied therapies, may help to reduce overall costs of care.

Penetration of efavirenz into the male genital tract: drug concentrations and antiviral activity in semen and blood of HIV-1-infected men.

Efavirenz is a potent non-nucleoside reverse transcriptase inhibitor, licensed for the treatment of HIV-1. Data on sanctuary site penetration are limited. Therefore, we measured efavirenz concentrations in the blood and semen of 19 HIV-1-positive men and found concentrations in seminal plasma averaged 10% of those in blood plasma. Furthermore, seminal plasma viral loads were suppressed by 24 weeks of therapy in all patients. These data suggest that efavirenz-containing regimens have antiviral activity within the male genital tract.

Pre-exposure prophylaxis for conception (PrEP-C) as a risk reduction strategy in HIV-positive men and HIV-negative women in the UK

Couples wishing to have biological children when one partner is HIV positive and the other is HIV negative present clinicians with complex clinical, social and ethical considerations. We established two multidisciplinary pre-conception services for HIV-positive individuals and their partners. We report the first UK use of pre-exposure prophylaxis for conception (PrEP-C) as part of an overall risk reduction strategy. Couples were counselled and written informed consent for PrEP-C was obtained. Patient demographics, HIV and medical histories were recorded. Males underwent baseline semen analysis and seminal HIV viral load testing. Females had full fertility screens. Both partners were screened for sexually transmitted infections. All couples used timed ovulatory intercourse (TOI). Tenofovir±emtricitabine was taken by the female at protocol designated times before±after TOI. Thirty-two male positive/female negative couples used the services. Thirteen couples have used PrEP-C (median age of male 41 years (range 32–56), female 31 (28–43); median CD4 533 (236–1194); all male plasma and seminal HIV viral loads were undetectable). Eleven pregnancies in 10 couples have resulted in 7 live births, 1 ongoing pregnancy and 4 miscarriages (5/40, 6/40, 10/40 and 1 twin 17/40) after a median of 2.5 attempts (range 1–5). PrEP-C was well tolerated with no discontinuations and no HIV transmissions. These data suggest that PrEP-C is a safe and effective option for serodiscordant couples wishing to conceive; a standardised protocol has been developed; data collection via a central database is under way.

The impact of once-nightly versus twice-daily dosing and baseline beliefs about HAART on adherence to efavirenz-based HAART over 48 weeks: the NOCTE study.

Objective:To determine the impact of once-nightly versus twice-daily dosing and beliefs about highly active antiretroviral therapy (HAART) on adherence to efavirenz-based HAART in antiretroviral-naive patients. Methods:A multicenter, open-label, 48-week, randomized controlled trial. Participants were randomized to receive once nightly didanosine plus lamivudine, or twice-daily combivir (zidovudine plus lamivudine) both in combination with efavirenz. Medication Event Monitoring Systems were used to compile drug-dosing histories. Beliefs about HAART (necessity and concerns) were measured at baseline using validated questionnaires. Perceptions of HAART intrusiveness were assessed after 4 weeks. Results:Eighty-seven patients were randomized (44 once-nightly and 43 twice-daily). Overall adherence was higher among the once-nightly arm (P = 0.0327). Eighty-one percent once-nightly and 62% twice-daily patients persisted with treatment for 48 weeks (P = 0.0559). Regimen execution was similar between both arms. Participants were significantly less likely to persist with HAART if their initial concerns about HAART were high relative to their perceived need for treatment (P = 0.025). Conclusions:The difference in adherence observed between once-nightly and twice-daily dosing was driven by a difference in persistence with treatment. Psychological preparation for starting HAART should address patients perceptions of necessity for HAART and concerns about adverse effects to maximize persistence with treatment.

Electronically monitored dosing histories can be used to develop a medication-taking habit and manage patient adherence

Nonadherence to prescribed medications can lead to medical complications, disease progression, hospitalizations, overestimated dosing requirements, impaired quality of life, and death, as well as incurring substantive costs for the healthcare system from suboptimal dosing during ambulatory pharmacotherapy. Adherence can be improved by helping patients build habits of taking prescribed medications, impacting day-to-day implementation of and persistence with rationally prescribed drug dosing regimens. Accurate, easily understood and personally relevant feedback is clearly relevant to many patients in this process. There is a clear-cut need for studies specifically designed to investigate interventions aimed at improving adherence, taking into account the sometimes complex nature of these interventions. Implementation of results from such studies can be expected to improve outcomes. For scientific progress to be maintained in this field, there is also a clear need for consistent use of a sound taxonomy for the dosing errors that comprise poor adherence (distinguishing between initiation, implementation and discontinuation), and for interventions performed to improve adherence.

Management of genital candidiasis. Review omitted issues on recurrent thrush.

EDITOR,--The British Society for Medical Mycologys review on the management of genital candidiasis fails to bring out some important points.1nnFirstly, the vulval vestibulitis syndrome is not included in the section on differential diagnosis. This, however, is the commonest misdiagnosis in our clinic for patients with recurrent thrush and must be considered in any patient who complains of superficial dyspareunia.2nnSecondly, the authors suggest that “recommended …

Apolipoprotein E-epsilon 4 and recurrent genital herpes in individuals co-infected with herpes simplex virus type 2 and HIV.

Apolipoprotein E (APOE) alleles have been associated with the severity of, or susceptibility to, infection by various microbes. We investigated the potential association between the APOE-ε4 allele and the rate of recurrence of genital herpes in patients who were HIV positive and herpes simplex virus type 2 (HSV-2) seropositive. The APOE-ε4 allele was significantly associated with recurrent genital ulceration independent of ethnicity, antiretroviral therapy and CD4 count (OR 8.3; 95% CI 2.4 to 28.5). To our knowledge, this is the first published study to demonstrate this association and suggests that APOE-ε4 may represent a future prognostic marker for symptomatic recurrence of genital herpes in individuals with HIV.

An analysis of baseline data from the PROUD study: an open-label randomised trial of pre-exposure prophylaxis

BackgroundPre-exposure prophylaxis (PrEP) has proven biological efficacy to reduce the sexual acquisition of the human immunodeficiency virus (HIV). The PROUD study found that PrEP conferred higher protection than in placebo-controlled trials, reducing HIV incidence by 86xa0% in a population with seven-fold higher HIV incidence than expected. We present the baseline characteristics of the PROUD study population and place the findings in the context of national sexual health clinic data.MethodsThe PROUD study was designed to explore the real-world effectiveness of PrEP (tenofovir-emtricitabine) by randomising HIV-negative gay and other men who have sex with men (GMSM) to receive open-label PrEP immediately or after a deferral period of 12xa0months. At enrolment, participants self-completed two baseline questionnaires collecting information on demographics, sexual behaviour and lifestyle in the last 30 and 90xa0days. These data were compared to data from HIV-negative GMSM attending sexual health clinics in 2013, collated by Public Health England using the genitourinary medicine clinic activity database (GUMCAD).ResultsThe median age of participants was 35 (IQR: 29–43). Typically participants were white (81xa0%), educated at a university level (61xa0%) and in full-time employment (72xa0%). Of all participants, 217 (40xa0%) were born outside the UK. A sexually transmitted infection (STI) was reported to have been diagnosed in the previous 12xa0months in 330/515 (64xa0%) and 473/544 (87xa0%) participants reported ever having being diagnosed with an STI. At enrolment, 47/280 (17xa0%) participants were diagnosed with an STI. Participants reported a median (IQR) of 10 (5–20) partners in the last 90xa0days, a median (IQR) of 2 (1–5) were condomless sex acts where the participant was receptive and 2 (1–6) were condomless where the participant was insertive. Post-exposure prophylaxis had been prescribed to 184 (34xa0%) participants in the past 12xa0months. The number of STI diagnoses was high compared to those reported in GUMCAD attendees.ConclusionsThe PROUD study population are at substantially higher risk of acquiring HIV infection sexually than the overall population of GMSM attending sexual health clinics in England. These findings contribute to explaining the extraordinary HIV incidence rate during follow-up and demonstrate that, despite broad eligibility criteria, the population interested in PrEP was highly selective.Trial registrationCurrent Controlled TrialsISRCTN94465371. Date of registration: 28 February 2013.