- 1.1 The PARTNER study and the Opposites Attract study
- 1.2 Implications of all available evidence
- 1.3 The Opposites Attract observational study
- 1.4 Methods
- 1.5 Study design and participants
- 1.6 The protocol
- 1.7 Procedures
- 1.8 Tell your friends! If you do not like it ... Tell it to enemies 😉
- 1.9 Like this:
- 1.10 Related
Initial evidence of a strong link between viral load do HIV of a seropositive partner and the risk of transmission to a seronegative partner came from observational studies in serodifferent heterosexual couples.
Evidence from a randomized study on the risk of HIV transmission in the context of viral antiretroviral therapy (ART) in heterosexual couples was provided by the HPTN 052 study, which reported a 96% reduction in linked transmissions in couples designated for premature (immediate) ) ART compared to couples assigned to late therapy. The continued monitoring at HPTN 052 from 2011 to 2016, after the ART offer from all participants, showed durability of the effect of ART; however, only 2% of couples were men who have sex with men (MSM).
The use of the self-reported condom was also high; participants reported not using condoms for a total of only 63 · 4 years of follow-up. To review previous evidence on the effect of antiretroviral therapy (ART) on the risk of HIV transmission, we searched PubMed articles published in English from 1 from January of 2000 to 7 of November of 2018 using MeSH. HIV "and" transmission "and" antiretroviral therapy "or" ART "and" men who have sex with men "or" gay or straight "or" serodiscordant "or" serodifferent ".
Previous studies, including a randomized controlled trial and several observational studies, provided estimates of the risk of HIV transmission through sexual intercourse in the context of virally suppressive ARV. Most evidence was in heterosexual heterosexual couples and varying levels of condom use were reported in many studies.
The PARTNER study and the Opposites Attract study
Some evidence on the risk of transmission in gay men was provided in the first phase of the PARTNER study and in the Opposites Attract study, but follow-up in these studies was not sufficient to exclude a significant upper limit of risk around the zero transmission study estimates in gay men.
The second phase of the PARTNER study bridges the gap in the evidence base for the risk of HIV transmission in heterosexual, same-sex couples where the HIV-positive partner is receiving supremely viral ARV and condoms are not used.
At the end of follow-up, 15 new HIV infections occurred during two years of eligible follow-up, but none were phylogenetically connected within the couple. Thus, the transmission rate of HIV during the couple of years eligible was zero, although 76.000 reports of anal sex without a condom, with a low upper limit of 95% CI of 0.23 per 100 pairs of years of follow-up.
Our findings provide a level of evidence on viral suppression and risk of HIV transmission through unsafe sex for gay men, similar to that reported for heterosexual couples.
Implications of all available evidence
The results of the PARTNER studies, in addition to evidence from other studies in serodifferent couples, indicate that the risk of HIV transmission through sex without a condom in the context of suppressive ART is effectively zero for both homosexual men and heterosexual couples.
These results support the message U = U (undetectable equals non-transmissible), as well as promoting the benefits of initial testing and treatment.
The first phase of the PARTNER (PARTNER 1) study estimated risks for different types of sex and for a broader population. The study reported no 888-linked transmission in seropositive couples (548 heterosexuals and 340 gay couples) who reported sex with condom penetration during 1.238 pairs of years of follow-up when the HIV-positive partner was undergoing viral suppressive ART.
PARTNER 1 reported 439 pairs of years of follow-up in serodifferent gay couples with zero reported transmissions. However, due to the lower number of couple of years of cumulative follow-up for gay couples than for heterosexual couples, the upper limit of 95% CI for the transmission rate for gay men was relatively high (0 · 84 per 100 peer-years of follow-up), almost double that for heterosexual couples (0,46 for 100 couple-years of follow-up). These results equate to an upper limit of risk of an 119 infection coupled-years of follow-up for gay couples compared to an 217 infection coupled-years of follow-up for heterosexual couples and was arguably insufficient to provide the level of evidence needed to support as a fully effective HIV prevention intervention in MSM.
The Opposites Attract observational study
It also reported zero cases of HIV transmission in MSM couples during 232 pairs of years of follow-up when anal sex without a condom was reported, the HIV positive partner was virally suppressed and the HIV negative partner did not use pre-exposure prophylaxis (PrEP), with a reasonably high 95% upper CI limit of 1 · 59 per 100 follow-up pairs for transmission rate.
The main objective of the second phase of the PARTNER (PARTNER2) study was to produce a similar level of evidence for risk of transmission through anal sex without a condom among men with suppressor ART (defined as viral load of HIV-1 RNA <200 copies per mL ) for that spawned for heterosexual couples in PARTNER 1.
Study design and participants
The PARTNER study was a multicenter, observational study of serodifferent couples who, before enrollment, did not always use condoms, and the HIV positive partner was on HAART. The 1 phase of the study recruited and accompanied heterosexuals and seropositive heterosexual couples from 15 from September from 2010 to 31 from 2014 in May.
From 1 from June of 2014 to 31 of July of 2017, the second phase of the study recruited gay men only different couples. The methods for the PARTNER study and the results of the first phase were previously published.
From 15 from 2010 from September of 31 to 2017 from July of July, we recruited 75 gay and serodiférico male couples clinical sites in 14 European countries. The participating clinic staff asked HIV-positive patients about ART if they had had sex without a condom with an HIV-negative partner and if they wanted to participate in a transmission study. Serodifiable couples (HIV-positive men with their HIV-negative male partner) were eligible to participate if both partners had 18 years or older; partners reported having penetrative sex with each other without condoms in the month prior to enrollment; the HIV-positive partner should remain on ART; partners expected to have sex again in the coming months; and both partners agreed to participate. The partners signed separate informed consent forms, which included identification of the partner by name. Tracking ended in 30 on April 2018. Follow-up was interrupted if the partnership ended, the couple moved, or if one partner withdrew consent, but not for changes in the use of condoms or ART.
all informed consent forms and participant information materials were submitted and approved by the ethics committee (IRB) or independent ethics committee (IEC) at each clinical site. Ethical approval was obtained in the country for all sites involved in the study. In addition, any changes to the study protocol were submitted and approved by each site's ethics committee (IRB or IEC).
The procedures of the study were described previously.
Os data were collected at baseline and then every 4-6 months during study visits. Detailed information was obtained at the beginning and at each follow-up visit through self-filled questionnaires on sociodemographic data; adherence to ART; frequency and type of sexual activity between partners (since last visit); symptoms and diagnoses of other sexually transmitted infections (STIs); use of PrEP or post-exposure prophylaxis (PEP); and injecting drug use. Seronegative partners were asked if they had had unprotected sex with someone who had not been their HIV positive partner in the study since their last visit and the HIV status of other partners, if known.
For the HIV-positive partner, the ART regimen, the cell count CD4 and the HIV-1 RNA load in current and recent plasma were recorded on a clinical case report form at the beginning and at each visit. The HIV-negative partner was asked to test for HIV every 6–12 months; a combined HIV antigen-antibody test was recommended to increase diagnostic sensitivity in early infection. The HIV-1 RNA viral load in plasma was measured in the HIV-positive partner according to routine care every 6-12 months, using the local diagnostic laboratory. The results were included in the case report forms and sent after each partner's visit by the study team to the study center.
If a seronegative partner became HIV positive, the HIV-1 in. e env of sequences were obtained from the HIV-1 RNA of the seroconverted partner recovered from the plasma and from the HIV-seropositive partner in the virally suppressive HIV-1 cell DNA recovered from the peripheral blood mononuclear cells. As e env sequences were generated by the Sanger sequencing (in an ABI 3730xl DNA analyzer, Thermo Fisher, Warrington, UK) supplemented by deep sequencing of plasma HIV-1 RNA by Illumina (MiSeq, Illumina, Essex, UK). with available plasma samples.
All sequencing tests were conducted at the University of Liverpool (Liverpool, UK). The maximum likelihood and Monte Carlo inferences of the Bayesian Markov chain and their relevant statistical support were determined with RAxML-HCP2 version 8 and MrBayes version 3.2.6, respectively, as previously described.
The primary analysis was the estimate of the incidence rate of HIV transmission through anal sex without a condom, calculated as the number of phylogenetically linked HIV infections (ie transmission of the seropositive partner to the study) occurring during the eligible couple. years of follow-up divided by pairs of eligible years of follow-up. Two years of follow-up were time periods defined by HIV tests and corresponding questionnaires on sexual behavior in the HIV-negative partner. These pairs of years were eligible for inclusion in the analysis of this study if couples had sex without a condom during the period (reported at the end of the time by the seronegative partner, or by the HIV-positive partner if the HIV-positive partner did not complete the question) ; PEP or PrEP was not reported by the HIV-negative partner during the period; the most recent viral load of HIV-1 RNA in the HIV-positive partner was measured in less than 200 copies per mL and in the last 12 months at all points measured in the period; and tracking occurred before 30 April 2018 (date of censorship).
In This Study Cannot Be Used PEP or PrEP (…)
Pairs of follow-up years may be ineligible for one or more reasons; the choice of the primary reason for ineligibility was prioritized in the following order: (1) PEP or PrEP used; (2) The seronegative partner (or the seropositive partner if the seronegative partner did not respond) did not report sex without a condom; (3) HIV seropositive partner's most recent viral load over 200 copies per ml; (4) data on missing sexual behavior; (5) no viral load available last year for each day in the time period; and (6) no HIV testing from the HIV-negative partner at the end of the time period or later in time. Two-sided 95% ICs for the transmission incidence rate were calculated using exact Poisson methods. The missing data were not imputed and the analysis was performed only on the available data. The data were analyzed using the SAS version 9.4.
In terms of sample size calculation, the PARTNER2 study was designed to assess whether the risk of transmission in the context of virally suppressive ARV was below an acceptably low level, defined as an 500 infection years-pair follow-up, corresponding to one upper limit for bilateral 95% IC of HIV transmission rate between 0 couples · 2 per 100 paired-years of follow-up. In the absence of interrelated infections, we determined that we needed 1770 pairs-years of follow-up eligible to achieve a bilateral upper limit of two-sided CI. Based on the results of PARTNER 1, we plan to recruit 450 couples with more than 27 months into PARTNER2. Assuming a retention rate of 85%, this would have allowed us to accumulate 2082 pair-years of follow-up through PARTNER 1 and PARTNER2, of which 85% were considered eligible (based on intermediate results) for the primary analysis.
Role of the FINANCING
The study lenders had no role in study design, data collection, data analysis, data interpretation or report writing. The corresponding author had full access to all study data and had final responsibility for the decision to submit for publication.
Between 15's September 2010 and 31's July 2017, were recruited 972 gay couples (477 couples during the PARTNER 1).
By the end of 30's April 2018 follow-up, a total of 2072 pairs of years of follow-up were accumulated (556 couple-years of follow-up during PARTNER 1), with an estimated abandonment rate of 25 per 100 pairs - follow-up.
Reasons to leave the study were the couple separated (213 [43%] from 499 couples), one or both partners moved away (33 [7%]), consent was withdrawn (54 [11%]), 2
- Study consent for two years has expired (21 [4%]), or the couple is no longer eligible (ten [2%]).
- The reason for abandoning the study was not available for 168 (34%) couples.
- 479 pairs of follow-up years were ineligible for inclusion in the analysis for the following reasons:
- no sex without a condom was reported (153 [32%] of 479 pairs-years of follow-up);
- use of PEP or PrEP (115 [24%]);
- HIV viral load data not available (86 [18%]);
- lack of data on whether sex without condom was reported (91 [19%]);
- viral load in HIV positive partner over 200 copies per ml (19 [4%]);
- or no HIV testing available from the HIV-negative partner (15 [3%]).
1593 (77%) pairs of follow-up years were eligible and contributed by 782 couples, with 439 couple-years follow-up contributed by 340 couples during the 1 PARTNER.
Unless otherwise noted, the following results are focused on the 782 couples who provided two years of eligible follow-up.
The median years of follow-up eligible per couple was 2 · 0 years (IQR 1 · 1-3 · 5). 1523 (96%) of the eligible follow-up peer-years were during the periods when the most recent HIV-1 plasma RNA measure in the HIV-positive partner was less than 50 copies per ml; the remaining 70 (4%) were in periods where the most recent measure was between 50 and 200 copies per mL.
The basic characteristics of participants who contributed to the eligible pair of years of follow-up are shown in table 1.
The median age was 38 years (IQR 31-45) in HIV-negative participants and 40 years (33-46) in HIV-positive partners.
Three trans men were included, one HIV negative and two HIV positive.
19 (2%) of 782 seropositive and 33 (4%) of 782 seronegative men reported that they were bisexual. HIV-negative men reported having unsafe sex with their HIV-positive partners for a median of 1 · 0 years (IQR 0 · 4-2 · 9) before inclusion in the study.