The moderately strong effects of HIV on HSV-2 (scenario 2a) increased the incidence of recognized herpetic ulcers from 5.9 to 7.4 per 100 person-years between 1980 and 2000. Combined with the relatively large decrease in the incidence of chancroid due to selective AIDS-related mortality, these effects increased the proportion of recognized GUD attributable to HSV-2 from 28% to 35%. In absolute terms, the increase in herpetic ulcer incidence counterbalanced the decrease in GUD incidence due to selective HIV-attributable mortality. As a result, HSV-2 seroprevalence and the overall incidence of GUD (of any etiology) remained stable between 1980 and 2000. Similar but more pronounced shifts in GUD etiology were predicted for scenario 2b, involving very strong effects of HIV. Here, the fraction of GUD attributable to HSV-2 increased to 48%. The absolute incidence of herpetic ulcers increased from six to 13 per 100 person-years, whereas the HSV-2 seroprevalence increased from 48% in 1980 to 58% in 2000.
Behavior change (scenario 3) reduced the incidence and prevalence of chancroid and syphilis considerably and rapidly (Figs. 3 and 4). The rates for chancroid decreased more markedly than those of syphilis because of its lower reproductive number. 47 Both HSV-2 seroprevalence and the incidence of herpetic ulcers decreased relatively little (from 48% to 39% and from 5.9 to 4.8 per 100 person-years, respectively). Since HSV-2 is a lifelong infection with a high baseline prevalence and recurrent nature, herpetic ulcerations can be reduced only by reductions in new infections in the youngest age groups. Therefore, it takes a long time for a decrease in HSV-2 transmission to have an impact on the incidence of herpetic ulcers at a population level. As a result of the large decrease in chancroid relative to the occurrences of herpes and syphilis, the proportion of recognized incident GUD attributable to HSV-2 increased from 28% in 1980 to 56% in 2000, whereas the proportion caused by chancroid decreased from 64% to 28%.
In a fourth scenario, combining behavior change and moderately strong effects of HIV, the incidence of herpetic ulcers remained unchanged over time, whereas that of chancroid and syphilis decreased, increasing the proportion of GUD attributable to HSV-2 to 61% by year 2000.
To explore the robustness of the results, we assessed their sensitivity to variations in model assumptions on HSV-2 and its possible interactions with HIV.
Of the parameters tested, the average duration of the early latent phase, the probability distribution function assumed for this duration, and the interval between recurrent ulcers were the most important determinants of HSV-2 seroprevalence and ulcer incidence levels. Although halving durations considerably reduced HSV-2 seroprevalence, doubling them did not substantially increase seroprevalence, because of saturation. In all simulations, the gender difference in HSV-2 seroprevalence was insensitive to the relative efficiencies of male-to-female and female-to-male transmission, indicating that its population distribution is mainly determined by sexual behavior patterns. Across all quantifications, behavior change shifted GUD etiologic distributions much more than moderately strong biologic effects of HIV. Of the different possible effects of HIV, that on the frequency of herpetic recurrences had the greatest impact on GUD etiology. Of the two assumed components of behavioral change, a 25% reduction in relationship-formation rates had more of an impact on GUD etiology than did a 25% reduction in prostitute visits.
In order to simulate both observed HSV-2 seroprevalences among adults in SSA (≥45%) and plausible frequencies of herpetic recurrences (<5 per 100 person-years), a high level of asymptomatic HSV-2 transmission had to be assumed. This finding supports the empirical evidence that a large proportion of herpetic ulcerations go unrecognized and that these contribute substantially to transmission. 49,54,55
Simulated HSV-2 epidemiology and GUD etiologic distribution were robust against most uncertainties in the natural history of HSV-2 (sensitivity analysis). This corroborates findings with simpler transmission models, in which interventions that had an impact on HSV-2 infectivity and ulceration had little influence on seroprevalence levels. 79,80 The duration of the early latent phase, during which ulcers recur, and the variability of this duration within the population were critical, however. Better data about these parameters, from long-term follow-up studies of unselected populations, would improve understanding of the transmission dynamics of HSV-2.
The model showed that realistic prevalences of HSV-2 and syphilis are consistent with an incidence of recognized GUD as high as 20 per 100 person-years. The simulated fraction of the population with recognized GUD in the last year, in contrast, was only 9% (scenarios 1 and 2), corresponding with proportions reported for SSA populations. 20,37 The difference between the incidence rate and the proportion with ulcers is the result of recurrence of ulcers (such as for HSV-2) and reinfections (such as for chancroid), as well as of clustering of ulcers caused by different STD, because of shared risk factors.
In both scenario 2b and scenario 3, the proportion of GUD attributable to HSV-2 increased considerably during the HIV epidemic (from 28% to 48% and 56%, respectively), resulting in GUD etiologic distributions in year 2000 (Fig. 5) in the range of those observed in advanced HIV epidemics. In Uganda, 75% to 85% of reported ulcers of which the cause was known were attributable to HSV-2, 6% to 9% were due to chancroid, and 4% to 17% were due to syphilis. 37,64 In Malawi, the three infections accounted for about equal proportions of GUD. 90 In rural Zimbabwe, 32% of diagnosed ulcers were attributable to HSV-2, 47% to chancroid, and 22% to syphilis. 91
Seemingly very strong biologic effects (scenario 2b) had to be assumed to explain a shift in GUD etiology approaching that caused by apparently realistic magnitudes of behavior change (scenario 3), and only in scenario 2b would HSV-2 seroprevalence and GUD incidence increase in absolute terms. The limited sensitivity of HSV-2 epidemiology in the general population to enhancement of herpetic ulceration in HIV-infected patients is first explained by the fact that not all HSV-2–infected patients are infected with HIV. Even in a severe HIV epidemic, not all HSV-2–infected patients contract HIV, and those who do contract it die earliest, which limits the combined prevalence. Second, the majority of partners of patients infected with HSV-2 or HIV are already infected with HSV-2; thus, increased infectivity does not always increase transmission in the population. Long-term follow-up studies in HIV-positive and HIV-negative populations could help determine whether HIV truly enhances herpetic ulceration as strongly as assumed here.
We may have overestimated the increase in the proportion of GUD attributable to HSV-2 because the simulation did not allow for a possible enhancement by HIV disease of chancroidal ulceration. 7 Because of its low reproductive number, 47 the latter effect could markedly increase the spread of chancroid during HIV epidemics. It should also be noted that the simulated HIV epidemic was, at a prevalence of 31% in 2000, more advanced than in many SSA populations. For less severe epidemics, increases in herpetic ulceration due to HIV would be less. Furthermore, we assumed sexual activity to be unaffected by symptoms. If many patients with ulcers were to temporarily abstain or reduce the frequency of intercourse, 64,92 we may have overestimated the influence of herpetic ulceration on HSV-2 transmission. Conversely, we ignored an effect of HIV on the severity of herpetic ulcers, which might lead HIV-infected patients to more often recognize these. This may have caused our model to underestimate the shift in GUD etiology possible among clinical cases in severe, advanced HIV epidemics.
The simulated shifts in GUD etiology in scenarios 2b and 3 were mediated through different mechanisms, which had opposing effects on HSV-2 seroprevalence and the absolute incidence of herpetic ulcers, chancroid, and syphilis (Figs. 3, 4, and 5). Does comparison of these predicted concomitant effects with empirical data allow inference as to which scenario best reflects reality?
No data are available on HSV-2 seroprevalence over time periods spanning the course of SSA HIV epidemics. 2 One study showed an increase in seroprevalence in urban and rural Zaire between 1959 and 1985 (from 21% to 60% and from 6% to 32%, respectively). 39 But sampling for these surveys was among young men in 1959 93 and in undefined general populations in 1985, circumstances leaving doubts about their comparability in terms of age and risk profile. Moreover, this putative time trend occurred largely before the HIV epidemic in this region. For herpetic ulcer incidence, longitudinal data allowing assessment of time trends in SSA are also lacking. The contrast between scenarios 2b and 3 in their effect on the absolute incidence of herpetic GUD and HSV-2 seroprevalence therefore does not allow proper validation. Future population-based surveillance on trends in these indicators may help to solve this issue.
Data on time trends in bacterial ulcerative and nonulcerative STDs in several SSA settings are available, and some match the simulated reduction in rates of syphilis, chancroid, and recognized GUD in scenario 3. For example, the number of chancroid diagnoses decreased sevenfold in Harare between 1990 and 1998 2; prevalences of gonorrhea, chlamydia, and syphilis decreased twofold to threefold among women in Nairobi between 1992 and 1997 94; in Malawi there were 1.1-fold to twofold decreases in the prevalence of syphilis, trichomoniasis, gonorrhea, and genital ulcers between 1990 and 1996 95; and factory workers in Mwanza, Tanzania, reported 35% less GUD in 1994 than in 1991. 70
Comparison between empirical data and simulations on age patterns in HSV-2 seroprevalence suggests that the true effect of HIV on herpetic ulceration is less strong than assumed in scenario 2b. The simulated saturation of HSV-2 seroprevalence at ages 20 to 29 years in this scenario (Fig. 5) is inconsistent with available data from SSA populations. For example, in Ndola, Harare, and Kisumu, HSV-2 seroprevalence peaked above age 45 or 35 years for both sexes. 20,21 This inconsistency was apparent in spite of conservative assumptions about the relation between ulceration and infectivity, since we specified a nonzero infectivity throughout the early latent phase in between recurrences and ignored a possibly higher infectivity with the occurrence of recognized (more severe) ulcers than with unrecognized episodes. If HSV-2 infectivity in SSA populations would correlate more strongly with (recognized) ulcers than in these simulations, the specified strong effects of HIV would result in even more unrealistic age patterns. Behavior change, in contrast, did not produce unrealistic age patterns in HSV-2 seroprevalence, although the limited available epidemiologic data did not allow us to check whether this scenario fit better for populations with recorded behavior change than for populations without. For Ndola, the simulated decrease in HSV-2 seroprevalence among the young after reduction of risk behavior improved the fit for males but worsened it for females (Figs. 2 and 5). For this advanced HIV epidemic, scenario 4 (combining behavior change with moderately strong effects of HIV) fit observed age patterns in HSV-2 seroprevalence as well as scenario 1 (with no interactions) did.
The large influence of behavior change can explain why increases in HSV-2 as a cause of GUD are also pronounced in developing countries without severe HIV epidemics, such as Southeast Asia. 96–98 For example, in Thailand the incidence of clinical syphilis and chancroid decreased threefold and 20-fold between 1987 and 1993, 98 the period of the 100%-condom-use program that successfully constrained the spread of HIV. 99
The simulated reduction in partner-change rates is not the only form of behavior change that can underlie relative increases in herpes. With increased condom use, the shift in GUD etiology could be even more marked than with partner reduction, because condom efficacy is likely lower against HSV-2—which can cause lesions outside the condom-protected genital area—than against bacterial STDs.
Behavior changes have not been noted in all countries in which the etiology of GUD has changed, not in, e.g., South Africa. 2,14–16,100 Also, the only published reports on absolute increases in genital herpes—which, according to our simulations, could result in advanced HIV epidemics if biologic effects of HIV are strong and there are no behavioral responses—come from Singapore and India. 101,102 Because Singapore and India at the time of these studies did not have advanced HIV epidemics, these absolute increases cannot be explained by HIV-related immunosuppression. This suggests that risk reduction and, in severe HIV epidemics, HIV-related immunosuppression are not the main explanations of (relative) increases in HSV-2 in all countries. Increased detection of genital herpes because of greater awareness may well be another important factor.
Finally, improved antibiotic management of STDs may have contributed to relative increases in herpes, through decreases in syphilis and especially chancroid. Improved care for STDs probably contributed to GUD epidemiologic shifts in more developed (e.g., Southeast Asian) countries. 101 For SSA populations, whose treatment facilities, symptom recognition, and treatment-seeking behavior are much poorer, 103 it is questionable whether STD treatment has so far played an important role. However, improvement of STD treatment, coupled with population-based health education to improve clinic attendance, certainly has the potential to enhance ongoing trends in GUD epidemiology in this region.
Our results suggest that seeming increases in genital herpes in SSA are mainly relative—or artifacts reflecting changes in detection—rather than absolute. Even in severe HIV epidemics, the overall incidence of GUD and HSV-2 seroprevalence are unlikely to increase in absolute terms, because the effects of HIV-related enhancement of herpetic ulceration are at a population level easily offset by factors causing GUD to decrease, such as HIV-attributable mortality. Behavioral response to the HIV epidemic is a particularly potent cause of relative increases in herpes among patients with GUD, through rapid and large decreases in chancroid.
The increasing proportion of HSV-2 as a cause of GUD in patients presenting to clinics implies that, as long as antiviral therapy for HSV-2 is not evident in developing countries, education on the prevention of transmission and on avoiding possible consequences of ulcers, including enhanced transmission of HIV (e.g., through temporary abstinence or condom use), becomes an increasingly important component of STD management.
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