Sheila Morris

BACKGROUND: The level of evidence for HIV transmission risk through condomless sex in serodifferent gay couples with the HIV-positive partner taking virally suppressive antiretroviral therapy (ART) is limited compared with the evidence available for transmission risk in heterosexual couples. The aim of the second phase of the PARTNER study (PARTNER2) was to provide precise estimates of transmission risk in gay serodifferent partnerships. METHODS: The PARTNER study was a prospective observational study done at 75 sites in 14 European countries. The first phase of the study (PARTNER1; Sept 15, 2010, to May 31, 2014) recruited and followed up both heterosexual and gay serodifferent couples (HIV-positive partner taking suppressive ART) who reported condomless sex, whereas the PARTNER2 extension (to April 30, 2018) recruited and followed up gay couples only. At study visits, data collection included sexual behaviour questionnaires, HIV testing (HIV-negative partner), and HIV-1 viral load testing (HIV-positive partner). If a seroconversion occurred in the HIV-negative partner, anonymised phylogenetic analysis was done to compare HIV-1 pol and env sequences in both partners to identify linked transmissions. Couple-years of follow-up were eligible for inclusion if condomless sex was reported, use of pre-exposure prophylaxis or post-exposure prophylaxis was not reported by the HIV-negative partner, and the HIV-positive partner was virally suppressed (plasma HIV-1 RNA <200 copies per mL) at the most recent visit (within the past year). Incidence rate of HIV transmission was calculated as the number of phylogenetically linked HIV infections that occurred during eligible couple-years of follow-up divided by eligible couple-years of follow-up. Two-sided 95% CIs for the incidence rate of transmission were calculated using exact Poisson methods. FINDINGS: Between Sept 15, 2010, and July 31, 2017, 972 gay couples were enrolled, of which 782 provided 1593 eligible couple-years of follow-up with a median follow-up of 2·0 years (IQR 1·1-3·5). At baseline, median age for HIV-positive partners was 40 years (IQR 33-46) and couples reported condomless sex for a median of 1·0 years (IQR 0·4-2·9). During eligible couple-years of follow-up, couples reported condomless anal sex a total of 76 088 times. 288 (37%) of 777 HIV-negative men reported condomless sex with other partners. 15 new HIV infections occurred during eligible couple-years of follow-up, but none were phylogenetically linked within-couple transmissions, resulting in an HIV transmission rate of zero (upper 95% CI 0·23 per 100 couple-years of follow-up). INTERPRETATION: Our results provide a similar level of evidence on viral suppression and HIV transmission risk for gay men to that previously generated for heterosexual couples and suggest that the risk of HIV transmission in gay couples through condomless sex when HIV viral load is suppressed is effectively zero. Our findings support the message of the U=U (undetectable equals untransmittable) campaign, and the benefits of early testing and treatment for HIV. FUNDING: National Institute for Health Research.

BACKGROUND: The length of time that people with HIV on antiretroviral therapy (ART) with viral load suppression will be able to continue before developing viral rebound is unknown. We aimed to investigate the rate of first viral rebound in people that have achieved initial suppression with ART, to determine factors associated with viral rebound, and to use these estimates to predict long-term durability of viral suppression. METHODS: The UK Collaborative HIV Cohort (UK CHIC) Study is an ongoing multicentre cohort study that brings together in a standardised format data on people with HIV attending clinics around the UK. We included participants who started ART with three or more drugs and who had achieved viral suppression (≤50 copies per mL) by 9 months after the start of ART (baseline). Viral rebound was defined as the first single viral load of more than 200 copies per mL or treatment interruption (for ≥1 month). We investigated factors associated with viral rebound with Poisson regression. These results were used to calculate the rate of viral rebound according to several key factors, including age, calendar year at start of ART, and time since baseline. RESULTS: Of the 16 101 people included, 4519 had a first viral rebound over 58 038 person-years (7·8 per 100 person-years, 95% CI 7·6-8·0). Of the 4519 viral rebounds, 3105 (69%) were defined by measurement of a single viral load of more than 200 copies per mL, and 1414 (31%) by a documented treatment interruption. The rate of first viral rebound declined substantially over time until 7 years from baseline. The other factors associated with viral rebound were current age at follow-up and calendar year at ART initiation (p<0·0001) and HIV risk group (p<0·0001); higher pre-ART CD4 count (p=0·0008) and pre-ART viral load (p=0·0003) were associated with viral rebound in the multivariate analysis only. For 1322 (29%) of the 3105 people with observed viral rebound, the next viral load value after rebound was 50 copies per mL or less with no regimen change. For HIV-positive men who have sex with men, our estimates suggest that the probability of first viral rebound reaches a plateau of 1·4% per year after 45 years of age, and 1·0% when accounting for the fact that 29% of viral rebounds are temporary elevations. INTERPRETATION: A substantial proportion of people on ART will not have viral rebound over their lifetime, which has implications for people with HIV and the planning of future drug development. FUNDING: UK Medical Research Council.

We set out to quantify the changes in HIV-related morbidity and mortality associated with the clinical use of antiretroviral therapy via prospectively collected patient-related events (admissions, bed days, deaths, WHO stage 3 and 4 events and drug costs) on all HIV patients known to the Regional Infectious Disease Unit (RIDU) from 1 January 1987 to 31 December 1996. The introduction of zidovudine monotherapy in 1987 for those with AIDS was associated with a subsequent decline of inpatient activity for 2 years: in 1989 there was a 23% reduction in bed days but only a 6% reduction in admissions. A further dramatic decline of patient-related events in those with AIDS was noted during 1996 following the introduction of combination therapy, a 39% reduction in admissions, 44% reduction in bed days, 54% reduction in stage 4 events, 33% reduction in WHO stage 3 events and 40% reduction in the death rate. Reductions were also observed for patients without AIDS including a 42% reduction in the rate of patients developing AIDS. Similar reductions were noted when the patients were classified by immunological instead of clinical status although data for 1997 suggest an increase in patient-related activity for those with CD4 counts >200 cells/microl possibly as a result of low levels of anti-HIV therapy. The introduction of combination therapy for HIV has to date led to a minimum saving of one inpatient bed per 100 patient years which helped defray the cost of combination therapy. Although we cannot imply causality from an observational study, dramatic reductions in patient-related activity were associated with the introduction of combination therapy into clinical practice. The ultimate extent and duration of this effect cannot as yet be predicted and caution is required since similar reductions were noted with zidovudine therapy which were unfortunately time limited.

OBJECTIVES: To investigate the potential for CD4+CD8+ T cells [CD8 double positive (CD8 DP)] T cells to form a reservoir of HIV-1 following HAART through measurement of the rate of decay of infected CD4/CD8 DP T cells. METHODS: HIV-1 proviral loads in highly pure CD4 and CD8 DP T cells were determined for study subjects before and after 200-400 days of therapy and HIV-1 DNA decay rates were calculated. RESULTS: Before therapy, HIV-1 proviral load in CD8 DP correlated negatively with CD4 cell count. Decay rates of HIV-1-infected CD4 and CD8 DP T cells were similar. Rates for CD8 DP T cells correlated with the time to suppression of viral replication, whereas no such relationship was true for CD4 cell decay rates. A significant reduction in activated cells was observed for both cell types. The action of HAART on HIV-1 replication was similar for both CD4 cells and CD8 DP T cells, although the rate of clearance of infected CD8 DP T cells appeared more critical for a rapid reduction in plasma viral load. Although the size of the CD8 DP T cell reservoir in peripheral blood was smaller relative to that of CD4 cells, HAART did not completely clear HIV-1 infection from this cell subset. CONCLUSION: This study confirmed that CD8 DP T cells are a major reservoir for HIV-1 in vivo and, therefore, represent a potential reservoir for HIV-1 during HAART, in a manner analogous to that of CD4 T cells.

PURPOSE: To investigate changes in immune cell subsets in the peripheral circulation of a male population occupationally exposed to ionizing radiation. MATERIALS AND METHODS: Peripheral blood samples were taken from 194 male workers with cumulative exposures of >200 mSv (mean exposure 331.5 mSv, mean age 51 years) and from a reference population of 131 male workers with cumulative exposures of <27.5 mSv (mean exposure 13.9 mSv, mean age 47 years). Samples were analysed by flow cytometry for T- and B-cell total counts and for the T-cell subset percentages of CD4+ (helper T-cells), CD8+ (cytotoxic T-cells) and CD3+/HLA-DR+ (activated T-cells). RESULTS: Comparison of the >200 and <27.5 mSv exposure groups using linear regression analysis showed no statistically significant differences between the two groups for T-cell total count, B-cell total count or for percentages of the T-cell subsets CD4+, CD8+ or CD3+/HLA-DR+ and CD4+:CD8+. However, statistically significant increases in both T- and B-cell total counts were observed within the two exposure groups and data pooled from both groups when non-smokers (never and ex-smokers) were compared with current smokers. For pooled data T-cell total count increased in smokers by 35% (p=0.0001) and B-cell total count increased by 37% (p=0.0004). CONCLUSIONS: No significant immunological effects were observed in male radiation workers with cumulative exposures of >200 mSv when compared with a reference population with cumulative exposures of <27.5 mSv, although highly significant increases in both T- and B-cell total counts were observed in smokers compared with non-smokers.