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).
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.
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).
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.
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).
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
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.
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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