Erasmus Smit

Stopping antiretroviral therapy

Combination antiretroviral regimens continue to fail in some patients [1,2]. Here we consider a factor that may be important; i.e. how patients stop therapy. We previously postulated that if one drug in a regimen has a significantly longer half-life than others, and all agents are stopped simultaneously [3] then the patient will be taking essentially ‘functional monotherapy’ after the shorter half-life drugs are eliminated (Fig. 1a). The probability of resistance emerging will depend on: (i) the drug’s genetic barrier; (ii) the magnitude of viral replication when the drug remains at a concentration capable of inducing resistance; and (iii) the length of time the drug remains in the zone of resistance selection.

Dynamics of raltegravir resistance profile in an HIV type 2-infected patient.

The evolutionary dynamics of RAL resistance in the HIV-2 virus were examined through population and clonal sequence analysis of the IN from baseline, during treatment, and after stopping RAL therapy. The treatment failure of an RAL regimen in the HIV-2 patient studied was associated with the emergence of mutations via the N155H resistance pathway and subsequent switching to the Y143C mutational route. This study has also identified four novel secondary mutations, Q91R, S147G, A153G, and M183I, not previously reported in HIV-1 patients failing RAL therapy. Resistant variants involving the Y143C pathway were noted to have persisted beyond 4 weeks following the cessation of RAL therapy. All resistance-associated mutations were lost at 20 weeks after stopping RAL therapy. Our findings provide evidence supporting the supposition that substantial cross-resistance between strand transfer IN-Is is likely in HIV-2 as shown in HIV-1.

Genetic Diversity of Integrase (IN) Sequences in Antiretroviral Treatment-Naive and Treatment-Experienced HIV Type 2 Patients

Two potent integrase inhibitors (IN-Is), raltegravir (RAL, MK-0518) and elvitegravir (EGV, GS-9137), have been shown to be potent inhibitors for HIV-1 and resistance mutations have been identified in HIV-1 clinical trials. In this study, sequences from 11 HIV-2 patients were examined for IN polymorphisms. The primary mutations associated with RAL and EGV resistance were not detected despite the genetic variability among clinical isolates. Our study provides basic information on genotypic susceptibility of HIV-2 to RAL and EGV and supports the suggestion that RAL and EGV could be considered as a new therapeutic option for treating HIV-2-infected patients.

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.

Second-line protease inhibitor-based antiretroviral therapy after non-nucleoside reverse transcriptase inhibitor failure: the effect of a nucleoside backbone

BACKGROUND Virological failures on combined antiretroviral therapy still occur. Boosted protease inhibitor ( Pl/r)- based therapy is a commonly used option after non-nucleoside reverse transcriptase inhibitor ( NNRTI) failure, but whether two fully active nucleoside reverse transciptase inhibitors (NRTIs) are required is unknown. We investigated the effect of an NRTI backbone in individuals receiving Pl/r after failing NNRTI-based combined antiretroviral therapy. METHODS A longitudinal analysis of the UK Collaborative HIV Cohort (CHIC) and the UK HIV Drug Resistance Database to identify individuals who failed first-line NNRTI and two NRTIs, and switched to Pl/r-based therapy between January 1999 and December 2008 was conducted. We investigated the effect of NRTI on suppression. RESULTS In total, 470 individuals met study criteria: 19.6%, 34.5% and 46.0% started 0, 1 or ≥ 2 NRTIs, respectively. Median CD4+ T-cell count was 223 cells/mm3 and HIV-RNA was 4.3 log10 copies/ml; 246 (52.3%) underwent genotyping before switch. virological failure occurred in 10.9% and 13% after 48 and 96 weeks, respectively. In multivariable analysis, heterosexual risk group and HIV RNA were independently associated with virological failure; higher CD4+ T-cell count was protective (HR= 0.92). Number of new NRTIs or genotypic sensitivity score of backbone had no effect on treatment success rates when modelled as categorical or continuous variables. CONCLUSIONS Successful treatment with a second-line Pl/r may not require two active NRTIs. If replicated in clinincal trials, these findings could guide future recommendations.

Darunavir concentrations exceed the protein-corrected EC50 for wild-type HIV in the semen of HIV-1-infected men.

Variable antiretroviral drug penetration into the genital tract may contribute to the differential evolution of HIV-1 and the emergence of drug resistance. We compared concentrations of darunavir in 34 time-matched blood plasma and seminal plasma samples from 18 HIV-1 positive men. Darunavir in seminal plasma were approximately 10–20% of that achieved in blood at matched time points postdrug ingestion. All seminal plasma darunavir were above the protein-corrected EC50 values for wild-type HIV-1.

An association between K65R and HIV-1 subtype C viruses in patients treated with multiple NRTIs.

Abstract Objectives: HIV-1 subtype C might have a greater propensity to develop K65R mutations in patients with virological failure compared with other subtypes. However, the strong association between viral subtype and confounding factors such as exposure groups and ethnicity affects the calculation of this propensity. We exploited the diversity of viral subtypes within the UK to undertake a direct comparative analysis. Patients and methods: We analysed only sequences with major IAS-defined mutations from patients with virological failure. Prevalence of K65R was related to subtype and exposure to the NRTIs that primarily select for this mutation (tenofovir, abacavir, didanosine and stavudine). A multivariate logistic regression model quantified the effect of subtype on the prevalence of K65R, adjusting for previous and current exposure to all four specified drugs. Results: Subtype B patients (n = 3410) were mostly MSM (78%) and those with subtype C (n = 810) were mostly heterosexual (82%). K65R was detected in 7.8% of subtype B patients compared with 14.2% of subtype C patients. The subtype difference in K65R prevalence was observed irrespective of NRTI exposure and K65R was frequently selected by abacavir, didanosine and stavudine in patients with no previous exposure to tenofovir. Multivariate logistic regression confirmed that K65R was significantly more common in subtype C viruses (adjusted OR = 2.02, 95% CI = 1.55–2.62, P < 0.001). Conclusions: Patients with subtype C HIV-1 have approximately double the frequency of K65R in our database compared with other subtypes. The exact clinical implications of this finding need to be further elucidated.

P118 Should we treat or rescreen patients first with equivocal chlamydia and gonorrhoea naat results

Background/introduction Equivocal NAAT results for Chlamydia and gonorrhoea (GC) cause treatment dilemmas for health professionals as there are no definitive management guidelines. Debate continues whether to rescreen and treat patients with equivocal results or rescreen the patient and await results before treatment. Aim(s)/objectives To investigate rescreening tests for equivocal results and establish when patients should be offered treatment. Methods A retrospective study of equivocal results from 2 GUM clinics between November 2013 and May 2014, and a third clinic between March 2010 and May 2014. HIV positive patients’ results were included. Paper notes or electronic systems were examined. Data was collected using a standardised proforma and analysed using excel software. Results 76 equivocal results (2.2% of positive results) were investigated. 62 patients (83.8%) attended recall appointments, 36 patients (58.0%) were offered treatment and rescreened, 14 (22.6%) were rescreened and awaited results prior to treatment and 2 patients (3.2%) were treated with no retest sent. 8 patients (16.1%) were treated due to a positive GC result at a second site alongside the equivocal result. Of the 54 equivocal results re-tested, 3 (5.6%) were positive and all of these resulted from equivocal GC tests (19 rescreened). All 35 rescreened equivocal Chlamydia tests were negative. Discussion/conclusion There is currently variation in how clinicians are managing equivocal results. The findings suggest that initiating treatment for Chlamydia before rescreening may result in over treatment. GC equivocal results are more likely to be positive on re-testing, thus clinicians should have a lower threshold for treating these at the time of rescreening.