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Heterosexual HIV-1 Infectiousness and Antiretroviral Use: Systematic Review of Prospective Studies of Discordant Couples

Baggaley, Rebecca F.a; White, Richard G.b; Hollingsworth, T. Déirdrea; Boily, Marie-Claudea

doi: 10.1097/EDE.0b013e318276cad7
Infectious Disease

Background: Recent studies have estimated the reduction in HIV-1 infectiousness with antiretroviral therapy (ART), but high-quality studies such as randomized controlled trials, accompanied by rigorous adherence counseling, are likely to overestimate the effectiveness of treatment-as-prevention in real-life settings.

Methods: We attempted to summarize the effect of ART on HIV transmission by undertaking a systematic review and meta-analysis of HIV-1 infectiousness per heterosexual partnership (incidence rate and cumulative incidence over study follow-up) estimated from prospective studies of discordant couples. We used random-effects Poisson regression models to obtain summary estimates. When possible, the analyses were further stratified by direction of transmission (man-to-woman or woman-to-man) and economic setting (high- or low-income countries). Potential causes of heterogeneity of estimates were explored through subgroup analyses.

Results: Fifty publications were included. Nine allowed comparison between ART and non-ART users within studies (ART-stratified studies), in which summary incidence rates were 3.6/100 person-years (95% confidence interval = 2.0–6.5) and 0.2/100 person-years (0.07–0.7) for non-ART- and ART-using couples, respectively (P < 0.001), constituting a 91% (79–96%) reduction in per-partner HIV-1 incidence rate with ART use. The 41 studies that did not stratify by ART use provided estimates with high levels of heterogeneity (I 2 statistic) and few reported levels of ART use, making interpretation difficult. Nevertheless, estimates tended to be lower with ART use. Infectiousness tended to be higher for low-income than high-income settings, but there was no clear pattern by direction of transmission (man-to-woman and woman-to-man).

Conclusions: ART substantially reduces HIV-1 infectiousness within discordant couples, based on observational studies, and could play a major part in HIV-1 prevention efforts. However, the non-zero risk from partners receiving ART demonstrates that appropriate counseling and other risk-reduction strategies for discordant couples are still required. Additional estimates of ART effectiveness by adherence level from real-life settings will be important, especially for persons starting treatment early without symptoms.

Supplemental Digital Content is available in the text.

From the aDepartment of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College London; and bDepartment of Infectious Disease Epidemiology, Faculty of Epidemiology and Population Health, London School Of Hygiene and Tropical Medicine, London, United Kingdom.

Submitted 12 October 2012; accepted 17 July 2012.

This work was supported by the Wellcome Trust (R.F.B., grant number WT082623MA), UK Medical Research Council (R.G.W., Methodology Research Fellowship grant number G0802414), the Bill and Melinda Gates Foundation (R.G.W., grant number 19790.01), the EU FP7 (R.G.W., grant number 242061), and Imperial College London Junior Research Fellowship Programme (T.D.H.).

The authors report no conflicts of interest.

Supplemental digital content is available through direct URL citations in the HTML and PDF versions of this article (www.epidem.com). This content is not peer-reviewed or copy-edited; it is the sole responsibility of the author.

Correspondence: Rebecca Baggaley, Department of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College London, St Mary’s Campus, Norfolk Place, London W2 1PG, United Kingdom. E-mail: r.baggaley@imperial.ac.uk.

HIV-1 remains among the world’s leading causes of mortality, with an estimated 2.7 million new infections in 2010.1 Treatment-as-prevention has been proposed as a much-needed new tool to prevent HIV transmission.2 Although the efficacy of antiretroviral therapy (ART) for reducing the risk of HIV-1 transmission between stable partners has recently been estimated in the landmark HIV Prevention Trials Network (HPTN) 052 trial,3 such results do not necessarily reflect what would happen in less controlled settings (with less intensive risk-reduction and adherence counseling, for example) or if ART was scaled up more widely as treatment-as-prevention. The objective of this study is to comprehensively review all prospective studies of discordant couples to summarize HIV-1 transmission estimates by level of ART use by the infected partner (index case). These include many early and observational studies that involve study populations more similar to real-life populations.

We examined studies that followed couples who were discordant by HIV-1 status, from the time of diagnosis of the index case. This design has some limitations, notably selection bias. Couples in stable partnerships may therefore be at lower risk of transmitting than those in the general population. In addition, these studies are subject to left censoring, or frailty selection, whereby the most vulnerable couples of the so-called “high and fast transmitters” rapidly become seroconcordant4,5 and therefore ineligible for recruitment. Combined, these factors may result in oversampling of less infective index cases and less susceptible partners who remain uninfected longer, leading to underestimates of infectivity. Nonetheless, this study design is often judged preferable for estimation of per-partnership transmission because the enrollment of monogamous couples avoids having to account for partners with unknown serostatus. In addition, the time of seroconversion of the susceptible partner can be determined more accurately than from cross-sectional studies. Studies with frequent follow-up can also provide more reliable information with less recall bias on frequency and type of contact.6

The aim of this study is to summarize HIV-1 infectiousness for discordant couples by level of ART use, through a systematic review and meta-analysis. Our first “within-study” analysis systematically reviews all prospective discordant-couple studies directly comparing couples in which the index receives ART with those not receiving ART (ART-stratified studies). Our second, broader analysis includes all prospective heterosexual discordant-couple studies to provide a comprehensive summary of infectiousness estimates and to compare HIV-1 infectiousness estimates by level of ART use among each study sample. We also investigate the potential influence of direction of transmission (man-to-woman and woman-to-man) and setting (high- and low-income countries) on HIV-1 infectiousness and potential causes of heterogeneity across study estimates.

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METHODS

Search Strategy

The systematic review was undertaken according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) checklist for review of observational studies.7 Details of the search are published elsewhere,6 with a subsequent update to 31 July 2011. Our search terms were intentionally broad to capture publications estimating HIV-1 infectiousness of all types and modes of transmission, for use in other HIV-1 infectiousness reviews.6,8–10 We searched bibliographies of relevant articles to find additional publications not identified by electronic search. The search was not limited to English language articles, and we translated articles from other languages where required. In addition, we searched abstracts from the previous 2 years (2010, 2011) of International AIDS Society, Conference on Retroviruses and Opportunistic Infections, and International Society of Sexually Transmitted Research on “discordant.” Further search details are given in the eAppendix (http://links.lww.com/EDE/A626).

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Selection Criteria and Data Extraction

We extracted data on two outcome measures of sexual HIV-1 infectiousness, cumulative incidence of infection over study follow-up periods and incidence rate after exposure to an HIV-1–infected partner; we focus our analysis on incidence rate. We included all empirical prospective studies reporting either type of estimate or studies from which such estimates could be derived. Infectiousness estimates for heterosexual sex (vaginal sex or vaginal and anal sex) are reported here; estimates for oral sex and for homosexual intercourse, with per-act transmission probabilities, are reported elsewhere.6,8,10

This analysis is reported in two parts. The first “within-study” meta-analysis included ART-stratified studies. The second analysis included studies in which infectiousness estimates were not stratified by the ART use of index cases (non-ART–stratified studies). We used these studies to compare estimates by level of ART use. Only the results from the control arms of randomized controlled trials (RCTs) of non-ART interventions were included (results from the intervention arm available on request). We excluded cross-sectional estimates, indirect estimates from transmission dynamics modeling studies, narrative or methodological reviews, abstracts pre-2000, and study estimates based on fewer than 10 subjects. Non-ART–stratified studies were categorized as no-ART-use if they: (1) reported <3% ART use by study participants; (2) did not report on ART use but follow-up was censored at 1996 or earlier11 for high-income countries or 2005 or earlier12 for low-income countries; or (3) did not state follow-up dates, and publication was before 1997 for high-income countries or before 2005 for low-income countries. All other estimates were classed as “any ART use.” We allowed for up to 3% ART use as a maximum level of contamination within the no-ART-use group.

Where publications have been superseded by more recent information, the later source was included, unless an earlier source provided a larger sample size. Each relevant publication was examined by two reviewers (R.F.B. and M.-C.B. or R.G.W.) who compiled information on estimates and on study and participant characteristics. Discrepancies were resolved by consensus. Where possible, couples reporting no sexual activity or 100% condom use were excluded. Nineteen authors were contacted to obtain additional information or to clarify potential overlap in study participants between publications; 10 responded. A list of all included and excluded studies is available on request.

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Data Analysis and Statistical Methods

Forest plots were used to explore graphically the heterogeneity among study estimates.13 Heterogeneity was also explored using Cochran’s Q statistic14 and I 2 statistic.15 If there was significant heterogeneity (using P < 0.05 as a guideline but taking into account sample size and without a strict cutoff), no overall pooled estimate was provided on forest plots. We explored potential causes of heterogeneity through subgroup analyses based on study-level characteristics: condom use, presence of sexually transmitted infections (STIs), HIV-1 infection stage of index (based on clinical stage or CD4 count data—see eAppendix, http://links.lww.com/EDE/A626 for classification methods), prevalence of male circumcision, study design (RCT/observational); and population characteristics: region (Americas and Europe/Africa/Asia) and country-level prevalence of male circumcision. There were insufficient data to investigate other risk factors such as HIV-1 viral load. We used forest plots to explore graphically the heterogeneity among random-effects summary estimates calculated for subgroups.13

Regarding condom use, STIs, and infection stage, we created aggregate study-level variables because of incomplete and noncomparable reporting of these risk factors among studies (see eAppendix, http://links.lww.com/EDE/A626 and figure legends for details). An ecologic analysis pairing estimates with country-level male circumcision prevalence data16 was used because of the lack of information on male circumcision in most studies.

Where relevant, we used random-effects Poisson regression models to obtain summary estimates for HIV-1 incidence rates and cumulative incidence, with 95% confidence intervals (95% CIs). For each study or stratum, the total number of events was considered to be Poisson distributed for a given sum of person-years. Poisson regression models were fitted with a logarithmic link function. Total exposure time (incidence rate) or initial number of couples at risk (cumulative incidence) per study was used as an offset variable, with γ-distributed random effects at the study level. Further details of the methods are provided in the eAppendix (http://links.lww.com/EDE/A626).

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RESULTS

Summary of Search

Fifty prospective studies of discordant couples were included (eFigure 1, http://links.lww.com/EDE/A626). Nine studies fit the inclusion criteria for the first analysis, with HIV-1 transmission stratified by ART use of the index case3,17–25 (one study was reported in two abstracts20,21). Forty-one non-ART–stratified studies provided estimates for the second analysis, reporting either no (n = 29)26–54 or any (n= 12)55–66 ART use. Eighteen studies were excluded based on eligibility criteria (study details available on request). Several publications were excluded because they were superseded by more recent articles. Although Musicco et al17 and Saracco et al59 are from the same study, both were included (Musicco for the first analysis; Saracco for the second) because the former reports estimates stratified by ART status, whereas the latter does not; the same was true for Donnell et al24 and Celum et al.28 Most studies reported estimates of both HIV-1 incidence rate and cumulative incidence.

Among all publications included in these analyses, more were from low-income (n = 34) than high-income (n = 17) countries (Cohen et al3 provide results from nine countries, only one of which is high-income, and therefore, the study is classified here as low-income). Seven publications reported results from RCTs: one study testing ART use of the index (early vs. delayed ART),3 one testing pre-exposure prophylaxis,67 one testing herpes simplex virus suppressive therapy (Celum et al,28 non-ART–stratified; Donnell et al,24 ART-stratified), one testing male circumcision for prevention of man-to-woman HIV-1 transmission,53 and two cluster RCTs of a behavioral intervention55 and an STI treatment intervention.43 The remainder were observational studies.

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ART-Stratified Studies (Within-Study Comparisons)

One of the nine studies reporting HIV-1 transmission stratified by ART use (Fig. 1)3,17–25 was excluded because the therapy was zidovudine monotherapy.17 An additional conference abstract reported stratification of ART use in the form of pre-exposure prophylaxis67; this study was included in the forest plot but not the pooled ART effect estimate. The included studies reported combined man-to-woman and woman-to-man transmission and were from low-income settings, except for one from Spain22 and the one combining results from nine study countries (of which one was high-income).3 All studies provided incidence rate estimates (or data from which such estimates could be derived), except Wang et al.23 Cohen et al3 was included, although it should be noted that a small number of homosexual couples were included in the analysis (2% men who have sex with men, <0.1% women who have sex with women). Four studies did not state cumulative incidence.19–21,25,67 Summary incidence rate was 0.2/100 person-years (95% CI = 0.07–0.7) among ART-receiving couples and 3.6/100 person-years (2.0–6.5) among non-ART–receiving couples (studies from all settings, n = 73,18–22,24,25; incidence rate ratio (IRR) = 0.09 [0.04–0.21], P < 0.001; Table), constituting a 91% (79–96%) reduction in per-partner HIV-1 incidence rate with ART use. Because only two included studies reported results stratified by direction of transmission,20,21,68 we did not perform stratified meta-analyses. Further details of studies are shown in eTable 2 (http://links.lww.com/EDE/A626).

TABLE

TABLE

FIGURE 1

FIGURE 1

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Non-ART–Stratified Studies (Between-Study Comparisons)

Infectiousness by ART Use

HIV-1 incidence rate estimates ranged from 0.0 to 17.4/100 person-years for high-income settings (Fig. 2) and from 0.0 to 33.7/100 person-years for low-income settings (Fig. 3). Forest plots highlight the considerable heterogeneity among study estimates for low-income settings (Fig. 3, P < 0.001 test for heterogeneity for all no-ART-use estimates and combined man-to-woman and woman-to-man any ART use; insufficient data for any ART use by direction of transmission). High-income settings were more homogeneous, probably due to the small numbers of estimates per strata (Fig. 2; for combined transmission: no ART use, I 2 = 33%, P = 0.110, n = 6; any ART use, I 2 = 0%, P = 0.764, n = 2; for man-to-woman transmission: no ART use I 2 = 0%, P = 0.388, n = 4; any ART use I 2 = 60%, P = 0.032, n = 2; and for woman-to-man transmission: insufficient estimates). This heterogeneity and lack of sufficient estimates for some strata prevent straightforward interpretation of summary estimates. We therefore omitted these from the forest plots but provided them in eTable 3 (http://links.lww.com/EDE/A626). However, although absolute values of summary transmission rate estimates by level of ART use may not be reliable, the IRR of 0.31 (95% CI = 0.14–0.69, P = 0.001) for difference in infectiousness, any versus no ART use (combined man-to-woman and woman-to-man, all settings), is compelling.

FIGURE 2

FIGURE 2

FIGURE 3

FIGURE 3

Study estimates in Figures 2 and 3 are presented in order of increasing ART coverage, but few non-ART–stratified studies reported the precise level of ART use among study participants (n = 12), and, thus, no strong dose-response relationship is observed (see eFigure 3, http://links.lww.com/EDE/A626 for additional plots). However, for the stratum with the most estimates (combined man-to-woman and woman-to-man transmission for low-income countries, Fig. 3A), there were sufficient data to analyze the IRR by ART level (Fig. 4). Changing the comparison from no versus any ART use to none/any versus 100% use decreased the IRR to 0.04 (95% CI = 0.005–0.36, P = 0.004).

FIGURE 4

FIGURE 4

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Infectiousness by Setting

Incidence rates tended to be smaller in high-income countries (Fig. 2) than in low-income countries (Fig. 3). There were many estimates of zero transmission rates from high-income countries, even among the no-ART-use studies.37, 40,42,50,52 Of the 15 high-income estimates, only three35,41,57 were ≥5.0/100 person-years. Robertson et al57 reported on any ART use (prevalence of ART use not stated), but study subjects came from a population where index cases were current or former intravenous drug users, and, therefore, there may be HIV risk from needle contamination. There is no obvious explanation for the high estimate from Laurian et al35 (9.7/100 person-years for partners of hemophiliacs), but the sample size was small (n = 17). Thirty-three percent of couples followed by Operskalski et al41 reported anal intercourse.

In contrast to the low estimates from high-income settings, there were many high incidence rate estimates from low-income settings (Fig. 3). For combined man-to-woman and woman-to-man transmission, only 11 of 24 (46%) estimates were <5.0/100 person-years,28,39,46,54,58,60–65 four of which were from no-ART studies.28,39,46,54 Two large studies of no ART use reported particularly low infectiousness estimates,28,39 and three small studies produced particularly high estimates.33,34,38 The high estimate from Hugonnet et al34 was from partners of people who seroconverted during follow-up and therefore included the period of high infectiousness associated with acute infection. The index cases in the study by Hira et al33 were mostly symptomatic (14% AIDS, 82% AIDS-related complex) and therefore also likely to be more infectious. The paucity of information reported by Mao et al38 regarding risk factors makes interpretation of their high estimate difficult. Low-income studies were also more recent and tended to be far larger than those from high-income settings, particularly the RCTs. There were eight any-ART-use studies,56,58,60–65 which tended to be more recent (published 2006–2011) than the no-ART studies (1990–2010).

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Infectiousness by Direction of Transmission

There was no clear pattern regarding HIV-1 infectiousness by direction of transmission, woman-to-man compared with man-to-woman. Of the publications providing man-to-woman and woman-to-man infectiousness estimates from the same study, seven26,29–31,33,34,41 reported no significant difference between them, with the eighth27 being significant before adjustment but nonsignificant after adjusting for age.

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Subgroup Analyses

We undertook subgroup analyses to identify sources for the heterogeneity of infectiousness estimates. However, there was a lack of comparable information on HIV-1 risk factors. For example, of the 22 studies reporting no ART use for combined man-to-woman and woman-to-man transmission, only five provided data on the prevalence of male circumcision. Few differences in summary estimates by subgroup reached statistical significance, and those that did may be due to chance. Nevertheless, the data available do allow trends to be identified. Subgroup summary estimates are plotted for no-ART-use studies from high- and low-income settings for combined transmission and for low-income settings for man-to-woman and woman-to-man transmission (eFigure 2A–D, http://links.lww.com/EDE/A626). There were insufficient data to provide meaningful plots for any-ART-use estimates and woman-to-man and man-to-woman no-ART-use estimates from high-income countries.

Summary incidence rate estimates were lowest for studies from Europe and the Americas (combined transmission, no ART use 3.6/100 person-years [95% CI = 0.4–32.6]), then Africa (7.7/100 person-years [5.5–10.7]), and highest for Asia (10.9/100 person-years [1.7–69.5]; eFigures 2A and B, http://links.lww.com/EDE/A626). There were no substantial differences in summary estimates by level of condom use and STIs. HIV-1 infection stage classified studies as having index cases who were more (high proportion of late-stage or acute-stage HIV-1) or less infectious. For the majority of strata, the “more-infectious” subgroup had the higher summary incidence rates, although this was not the case for combined transmission high-income estimates (but only three studies reported relevant data40,41,52) and for woman-to-man low-income estimates (five studies28,30,39,43,69). In the first case, Operskalski et al41 was an outlier with high infectiousness, as discussed above. In the second case, the only two studies in the “more infectious” subgroup had small sample sizes.39,69

Although male circumcision status was not well reported, we found that studies with higher prevalence levels had lower summary incidence rates. The ecologic analysis using country-level circumcision prevalence data found no difference in summary estimates for woman-to-man transmission from low-income settings (5.8/100 person-years [95% CI = 3.5–9.5]) for high-prevalence settings; 5.8/100 person-years [3.7–9.1] for low-prevalence settings, eFigure 2D, http://links.lww.com/EDE/A626). Pooled estimates by study type were higher for trials than for observational studies for combined and man-to-woman transmission and roughly equal for woman-to-man transmission, but interpretation is limited because of the small number of trials included.

The inconsistent reporting of risk factors for HIV-1 transmission across studies means that only univariate analysis was possible for the subgroup analysis. The trends identified by each HIV-1 risk factor are generally as expected and therefore explain some of the heterogeneity in study estimates within each stratum. For most subgroup pooled estimates, substantial heterogeneity remained (eg, combined transmission no-ART-use all settings: 13 of 15 pooled estimates had I 2 ≥ 50%, data not shown).

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DISCUSSION

HIV-1 Infectiousness with ART

Our systematic review and meta-analysis of per-partner HIV-1 infectiousness includes all published prospective studies of discordant couples and suggests a 91% reduction (95% CI = 79–96%) in infectiousness with ART use by the index case from ART-stratified observational studies. Our results from non-ART–stratified studies support this observation for populations that more closely resemble real-world settings. The IRR of 0.04 for 100% versus <100% ART use among index cases does not mean a 96% reduction in infectiousness. We are not comparing consistent use with zero use, we cannot directly compare populations from different studies conducted in different settings at different time points, and we are relying on two small studies representing 100% ART use.60,63 However, the estimate does demonstrate a striking reduction in transmission within discordant couples with ART use for observational studies. Together with the stratified study analysis, there is compelling evidence that ART reduces HIV-1 infectiousness for sexual transmission.

The HPTN 052 RCT provides gold-standard evidence of the efficacy of ART for reducing the risk of HIV-1 transmission, finding a 96% reduction in linked HIV-1 transmission events within heterosexual stable couples.3 Our analysis summarizing findings from all ART-stratified studies found a 91% reduction. The other ART-stratified studies included in our review are observational and tended to involve ART-receiving index cases with more advanced HIV-1 disease than untreated index cases, probably with less intensive risk-reduction and adherence counseling; thus, a slightly lower effect of ART is unsurprising. This proof of concept that ART does indeed reduce sexual transmission of HIV-1 is not enough to predict the population-level impact of ART interventions on HIV-1 spread. Such predictions would require more data on the effectiveness of infectiousness reduction with ART when adherence-promotion counseling is set at the more modest intensity characteristic of existing ART programs and would need to look back at the incidence rates from the non-ART–stratified discordant-couple studies reviewed here to estimate transmission rates within stable partnerships in real-world settings—again, without risk-reduction counseling being as intensive as now justifiably required for prospective HIV-1 studies.

Incidence rate estimates from no-ART-use studies seem to have reduced over time (eg, Fig. 3A, combined man-to-woman and woman-to-man transmission, low-income settings). It is difficult to estimate a “typical” transmission risk to use for HIV-1 projections because (1) it is difficult to define a typical discordant couple, (2) levels of counseling differ between studies, and (3) awareness among the general population of HIV/AIDS and risks for transmission varies by time and location. However, the 5–10/100 person-years incidence rates reported between 1992 and 2001 by the majority of low-ART, low-income studies is a reasonable starting point from which to base predictions of the impact of ART, or indeed, pre-exposure prophylaxis or other HIV-1 interventions, within discordant couples from low-income settings.

In 2009, Attia et al70 reviewed five cohorts reporting HIV-1 transmission rates among heterosexual discordant couples with ART-treated index cases, finding that no transmission events occurred in patients who were treated with ART and who had viral loads <400 copies/ml. Although our findings were not able to stratify risk by viral load of the index, maintaining a lower or undetectable viral load on ART probably reduces transmission risk even further.70 Since the report by Attia et al, a reanalysis of the Partners in Prevention data (represented in our analysis by Celum et al28 and Donnell et al24) has supported the findings by Attia et al, with higher viral load increasing risk of HIV-1 transmission.71 No transmission events were observed from index cases with undetectable viral load in their blood, but there were a small number from people with undetectable viral load in genital fluids.72 In addition to the ART-stratified trials, we looked at all prospective discordant-couple studies and provided estimates of per-partner incidence rate from older studies, many of which did not involve such intensive risk-reduction counseling. These older studies may provide more real-world incidence rates, more accurately reflecting conditions for discordant couples in the general population.

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Infectiousness by Setting

Rates of HIV-1 transmission to partners were generally higher in low-income than high-income countries. There may be several explanations, including differences in methodology, rates of monogamy, rates of circumcision, differences in the stage of the HIV-1 epidemic or the proportion of symptomatic cases, patterns of sexual behavior, prevalence of other STIs, and variations in viral strains. More recent studies have used more sophisticated phylogenetic analyses to exclude transmissions that originated outside the partnership (see, for example, Celum et al28 and Fideli et al31).

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Infectiousness by Direction of Transmission

There was no clear difference in HIV-1 infectiousness by direction of transmission. For high-income settings, this may be due to the lack of studies (only one incidence rate for woman-to-man transmission was identified). In low-income countries, a higher prevalence of HIV-1 cofactors such as STIs may mask a true biologic difference in HIV-1 infectiousness. These findings are consistent with results from a previous meta-analysis of per-sexual-act HIV-1 infectiousness.6

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Study Limitations

Transmission probabilities are affected by a combination of risk factors for the person transmitting the virus (infectiousness) and the partner acquiring it (susceptibility). Factors known to affect HIV-1 infectiousness include stage of infection,73 viral subtype,74 STIs,75 type of sexual act,76 and male circumcision.77 Therefore, average transmission probabilities will depend on the distribution of these measured and unmeasured risk factors, and it may not be appropriate to generalize across populations. Discordant-couple studies usually recruit monogamous couples, who may have lower prevalence and incidence of various risk factors than the general population (eg, lower incidence of STIs). Furthermore, self-reported data on sexual behavior are often inaccurate because of recall and social-desirability bias,78 leading to imprecise estimates of frequency of sexual contacts, condom use, and reports of monogamy. There is more potential for bias in our non-ART–stratified study comparison than our ART-stratified comparison because we are comparing different studies, where distributions of these risk factors will differ between populations by place and time.

Our HIV-1 cumulative incidence and incidence rates show considerable heterogeneity, likely due to different distributions in HIV-1 risk factors across study populations. Although a meta-analysis is presented, care must be taken with the interpretation of summary estimates from such heterogeneous data and from studies with such different patterns of risk factors. This meta-analysis is informative at a qualitative level, identifying trends in estimates between risk groups. However, with incomplete or noncomparable reporting of HIV-1 risk factors and cofactors, we cannot adequately control for differences among studies. For non-ART–stratified studies, our distinction of no and any ART use is based on inferences from the study dates. There was incomplete reporting on dates and on many other HIV-1 risk factors and cofactors, which we therefore could not adequately control for in our analysis. Our analysis by ART use is also limited by the ecologic nature of our measure: for studies with ART use between 0 and 100%, we do not know which of the transmitting and nontransmitting couples included index cases who received ART.

The quality and emphasis placed on risk-reduction counseling of participating discordant couples is likely to have varied substantially among studies and over time. For example, couples identified as discordant only retrospectively by Quinn et al43 may have different risk behavior patterns from those who were aware of their serostatus. Such study designs are unlikely to be replicated. In contrast, the RCTs had intensive levels of risk-reduction counseling.

It has been stated that “longitudinal studies of discordant couples are the preferred epidemiologic design for the investigation of heterosexual HIV transmission.”34 However, this design misses primary infection and involves left-censoring selection bias, selecting for couples with biologic or behavioral characteristics that impart a lower risk of HIV-1 transmission. Therefore, the rates derived are likely to underestimate the true average HIV-1 transmission risk. To avoid this bias would require prospective recruitment of concordant HIV-1–negative couples to measure transmission rates from the time of HIV-1 acquisition of the index case. Such a large trial would be so costly as to be unfeasible. The exceptions are the Rakai Project Study,43 which retrospectively identified those persons who were in stable partnerships and, as a result, has been able to provide HIV-1 transmission risk for the acute stage of infection73—although it seems unlikely that such a study design will be replicated.79 By overcoming left censoring, Quinn et al43 did indeed estimate a higher infectiousness than other studies: the third highest transmission rate of 16 man-to-woman low-ART resource-poor setting estimates (Fig. 3B) and the highest of 13 for woman-to-man estimates (Fig. 3C). The second exception is Operskalski et al.41 The extremely high incidence rate (17.4/100 person-years) would be even higher if we took into account the two couples who were concordant positive at recruitment and for whom time since sexual contact began was known, after a blood transfusion of the index (incidence rate 22.0/100 person-years).

Prospective discordant-couple studies are also limited either by the small number of participants or the small number of seroconversions resulting from dissolution of couples, intensive condom promotion, short follow-up periods, or falling rates of transmission over time because of behavioral change or exhaustion of susceptible persons. They cannot allow for partnerships that have broken up (which often happens after an HIV-1 diagnosis). Nonetheless, monogamous HIV-1–discordant couples provide the best means of estimating HIV-1 infectiousness for sexual transmission because they (in principle) eliminate contamination from outside sources. For the purposes of comparison (such as by ART use, setting, and direction of transmission), these limitations in study design are less important because they are applicable to virtually all studies. However, in the absence of better data, these transmission rates are also used to inform trials and modeling studies. Therefore, it is important to appreciate the biases, especially the likely underestimation in risk as a result of left censoring.

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Conclusion

ART reduces viral loads and thus has been believed to reduce infectiousness. In the last 5 years, studies have demonstrated that this reduction in infectiousness can be marked.3,80 Therefore, widespread access to ART has the potential to have an impact on HIV-1 transmission, both at the individual level (reducing transmission risk and thus allowing a safer route to conception for many couples) and, potentially, at the population level, as an HIV-1 prevention tool.2,81–83 The use of ART has been broadened from a therapeutic role to prevention, not only by reducing infectiousness as shown here, but also by its use as pre-exposure prophylaxis for reduction of susceptibility.84 Our study reinforces the results of previous studies and meta-analyses70,85 that have shown how ART can reduce a person’s infectiousness through sexual transmission in trial or intervention scenarios. The conditions under which this potential has been demonstrated do not seamlessly translate to a prediction of the effects of ART on real-life situations, whereas our meta-analysis, with its inevitable limitations, shows that real-world studies of such interventions can provide useful estimates of their likely public health benefit.

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Acknowledgments

We gratefully acknowledge James Goedert, Koya Ariyoshi, Steven Reynolds, Deborah Jones, Szonja Vamos, Breno Santos, and Maria Wawer for providing additional data. We also thank Elizabeth and Richard Baggaley, Dongmei Liu, Lorenzo Sabatelli, Kendra Wu, and Isaac Fung for translations.

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