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Effect of Coinfection With STDs and of STD Treatment on HIV Shedding in Genital-Tract Secretions: Systematic Review and Data Synthesis

Rotchford, Karen MBChB*; Strum, Willem A. MD, PhD; Wilkinson, David MBChB, MSc, MD

Sexually Transmitted Diseases: May 2000 - Volume 27 - Issue 5 - p 243–248
Original Articles

Objective: To determine whether coinfection with sexually transmitted diseases (STD) increases HIV shedding in genital-tract secretions, and whether STD treatment reduces this shedding.

Design: Systematic review and data synthesis of cross-sectional and cohort studies meeting predefined quality criteria.

Main Outcome Measures: Proportion of patients with and without a STD who had detectable HIV in genital secretions, HIV load in genital secretions, or change following STD treatment.

Results: Of 48 identified studies, three cross-sectional and three cohort studies were included. HIV was detected significantly more frequently in participants infected with Neisseria gonorrhoeae (125 of 309 participants, 41%) than in those without N gonorrhoeae infection (311 of 988 participants, 32%; P = 0.004). HIV was not significantly more frequently detected in persons infected with Chlamydia trachomatis (28 of 67 participants, 42%) than in those without C trachomatis infection (375 of 1149 participants, 33%; P = 0.13). Median HIV load reported in only one study was greater in men with urethritis (12.4 × 104 versus 1.51 × 104 copies/ml; P = 0.04). In the only cohort study in which this could be fully assessed, treatment of women with any STD reduced the proportion of those with detectable HIV from 39% to 29% ( P = 0.05), whereas this proportion remained stable among controls (15-17%). A second cohort study reported fully on HIV load; among men with urethritis, viral load fell from 12.4 to 4.12 × 104 copies/ml 2 weeks posttreatment, whereas viral load remained stable in those without urethritis.

Conclusion: Few high-quality studies were found. HIV is detected moderately more frequently in genital secretions of men and women with a STD, and HIV load is substantially increased among men with urethritis. Successful STD treatment reduces both of these parameters, but not to control levels. More high-quality studies are needed to explore this important relationship further.

*From the Centre for Epidemiological Research in South Africa, South African Medical Research Council, Hlabisa, South Africa; the †Department of Medical Microbiology, University of Natal, Durban, South Africa; and the ‡South Australian Centre for Rural and Remote Health, University of Adelaide and University of South Australia, Whyalla and Adelaide, South Australia, Australia

Reprint requests: David Wilkinson, Head, South Australian Centre for Rural and Remote Health, University of South Australia at Whyalla, Nicolson Avenue, Whyalla, Norrie, South Australia 5608, Australia. E-mail: david.wilkinson@unisa.edu.au

Received for publication June 8, 1999, revised October 14, 1999, and accepted October 20, 1999.

THE GLOBAL EPIDEMICS of sexually transmitted diseases (STD) and HIV share many epidemiologic features.1 Coinfection with an STD is associated with an increased risk of HIV transmission,2–5 and STD control is considered to be a critical component of HIV-prevention strategies.6 Although improved STD case management in Tanzania resulted in a 42% reduction in community HIV incidence,7 repeated rounds of mass-population treatment for STDs did not reduce HIV incidence in Uganda.8

The biologic mechanism through which STDs may promote HIV transmission is not yet fully defined.6 Although many studies have demonstrated that HIV shedding does occur in male and female genital secretions, the proportion of persons who shed HIV varies (1) according to the population studied; (2) over time in the same person; (3) by viral detection methods used; and (4) by the prevalence of different risk factors.9–55 Possible risk factors for increased shedding include high blood-plasma viral load, low CD4 count and advanced clinical illness, low vitamin-A status, hormonal contraceptive use, and concurrent STD.9–12,14–20,22–24,27,29,33,35,36 Antiretroviral therapy reduces genital HIV shedding.19,26,29,37,39 The concentration of HIV in genital secretions (viral load) may be a major factor influencing the likelihood of sexual transmission.55

What is the evidence that concurrent infection with a STD increases HIV shedding in genital-tract secretions, and that STD treatment reverses this shedding? We present a systematic review and data synthesis of the published literature.

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Methods

Criteria for Selecting Studies for Review

We selected only cross-sectional and cohort studies that met the predefined quality criteria typically used in a systematic review.56 In particular, we required studies to confirm a diagnosis of STD microbiologically. We required cross-sectional studies to report on a group of patients with a STD and a comparison group without a STD recruited from a similar source population.57 For cohort studies, we required repeat measures of HIV to be performed pre- and posttreatment in the STD group; in the non-STD group, we required the same repeat measures performed at a similar time apart. This is particularly important because several studies have shown that HIV shedding may be intermittent and highly variable in load over time, irrespective of STD or antiretroviral therapy.14,23,28,30

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Search Strategy

We searched MEDLINE using the search terms sexually transmitted disease, genital secretions, and human immunodeficiency virus. All references of retrieved articles were also searched.

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Review Procedure

Two authors (KR and DW) independently reviewed the identified studies and extracted data from reports of included studies. We gave particular attention to diagnostic methods, choice of study groups, and follow-up methods.

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Outcome Measures

Outcome measures were as follows: (1) proportion of patients with and without an STD who had detectable HIV; (2) HIV load in genital secretions of these groups; and (3) change in these measures following STD treatment.

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Statistical Analysis

Where possible, data were extracted directly from reports; otherwise, proportions were calculated from available information. First, data from the cross-sectional studies were plotted and pooled with Revman (version 3.01; Update Software, Oxford), stratified by infecting organism (Neisseria gonorrhoeae and Chlamydia trachomatis). Second, cohort studies were analyzed. Where possible, we report by infecting organism; otherwise, we refer to “any STD” if the authors did not identify individual organisms.

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Results

Included Studies

We identified 48 studies that reported on HIV and genital-tract secretions.9–55 Of these, only 14 studied the effect of genital infection or inflammation on HIV shedding.9–22 Of these 14 studies, 1 was excluded because it reported history of STD and did not document current STD21; 3 were excluded because markers of inflammation were reported rather than infection;19,20,22 1 was a subgroup of a larger (included) study17; 1 had no control group9; 1 was a case study;18 and in 1 study15 data were reported as the proportion of positive samples affected rather than the proportion of patients affected (repeat samples were taken from individual patients).

Thus, three cross-sectional studies12,13,16 and three cohort studies10,11,14 met our predefined inclusion criteria and were included in the review (Table 1).

TABLE 1

TABLE 1

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Cross-Sectional Data

All cross-sectional studies and the baseline cross-sectional data from the two cohort studies10,12–14,16 that reported HIV shedding in patients with N gonorrhoeae and C trachomatis were included separately in the first analysis (Table 2). The third cohort study did not report on individual organisms. In all five studies, HIV was detected more frequently among patients with N gonorrhoeae than among those without this type of infection; this difference was statistically significant in three studies. When data were pooled (Table 2, Figure 1), the difference between the proportion of patients with and without N gonorrhoeae infection who had detectable HIV was 9% (41% versus 32%; P = 0.004). There is substantial homogeneity among these studies, suggesting that pooling of data is appropriate (Figure 1).

TABLE 2

TABLE 2

Fig. 1

Fig. 1

In the four studies that reported on C trachomatis, only the largest study demonstrated a significant association with HIV shedding.14 Three of the studies demonstrate a similar effect, whereas the fourth has a wide confidence intervals due to the small sample size. Pooled data (Table 2; Figure 2) suggest that HIV shedding is less frequent in persons with C trachomatis infection (42% versus 33%), but this difference is not statistically significant (P = 0.13).

Fig. 2

Fig. 2

Cohen et al11 reported HIV shedding in 87% of men with any STD compared with 78% in those without any STD, but did not report on the proportion by infecting organism; further, this difference was not statistically significant (P = 0.14). Data on HIV load was only reported by Cohen et al.11 Median HIV load was greater in men with urethritis (12.4 × 104 copies/ml) than in those without HIV load (1.51 × 104 copies/ml; P = 0.04). HIV load was highest in men with N gonorrhoeae infection, whereas among those with C trachomatis infection, HIV load was similar to that among controls.11

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Cohort Studies

Only one of three cohort studies fully reported on the proportion of participants with detectable HIV in both the STD group (pre- and posttreatment) and the non-STD group (providing two measures a similar time apart). Similarly, only one study reported fully on HIV load in both groups. Ghys et al14 showed a modest reduction in the proportion of women with detectable HIV after successful STD treatment (39% to 29%; P = 0.05), whereas levels remained stable over time in the non-STD group (Table 3). The proportion with detectable HIV post-STD treatment (29%) remained higher than the proportion in the non-STD group (15-17%). Cohen et al11 reported a substantial reduction in HIV load following successful STD treatment in men, from 12.4 to 4.12 × 104 copies/ml at 2 weeks (P = 0.0001), whereas HIV load remained relatively stable in those without an STD (1.51−2.5 × 104 copies/ml; P = 0.42). Posttreatment viralload levels did not reach levels of the non-STD group.

TABLE 3

TABLE 3

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Discussion

This systematic review and data synthesis of observational studies reporting on the association between coinfection with a STD and HIV shedding in genital-tract secretions, and on the effect of STD treatment, failed to find many studies of high quality. This reflects the difficulty conducting this type of research.

Our pooled data suggest a modest association between HIV shedding and STD. The association is stronger for infection with N gonorrhoeae than for infection with C trachomatis. We note that the proportion of patients with detectable HIV is increased only modestly (from 32% to 41%) by coinfection with N gonorrhoeae. Similarly, data were only available from one study of appropriate design11 to suggest that HIV load is substantially increased in the genital secretions of men with urethritis. This study11 also suggests that viral load is higher among men with N gonorrhoeae infection (who have greater urethral inflammation11) than among those with C trachomatis infection. These observations are important because the infectivity of HIV through sexual transmission is directly related to HIV viral load in genital secretions, which is similar to that in parenteral and mother-to-child transmission.55

Furthermore, we found only limited data from studies of appropriate design to suggest that the proportion of patients with detectable genital HIV shedding falls after successful STD treatment.14 Despite a large sample size, the modest reduction from 39% to 29% was of borderline statistical significance. Also, the proportion of persons with detectable HIV after treatment (29%) remained almost double that of persons without an STD with detectable HIV (Table 3).

The evidence that HIV load in genital secretions is substantially reduced after successful STD treatment is stronger; however, only one study of adequate design reported on this.11 It should be noted that even 2 weeks posttreatment, viral load remained higher in the STD group than in the control group (Table 3). The few studies of appropriate design that we identified limit the confidence of these conclusions. It is worth noting that all studies are from Africa, and most are from Kenya. As such, there may be some concern about the generalizability of the results; further studies in different settings are warranted. We pooled data from men and women because we aimed to increase the power of our analysis and because we observed little heterogeneity in the data (Figures 1 and 2). As more data becomes available, metaanalyses of male and female data separately would be valuable.

The value of systematic review and metaanalysis of randomized controlled trials is now well recognized.56 The application of systematic review to observational studies is also recognized as valid; however, metaanalysis has a less prominent role because there is a real danger of producing precise, but spurious, results.58 We conducted a rigorous search for relevant studies, critically appraised study quality against predefined criteria,56 and only pooled data from studies that demonstrated little heterogeneity and that reported data consistently (e.g., by organism). As new data becomes available, this review can be updated.

Systematic review is also useful because it highlights important deficiencies in study design and reporting, which can be rectified in the future. We did not include several studies because of the lack of adequate control-group measures. This is important because HIV shedding in genital-tract secretions is frequently variable over time,14,22,23,30 and if any change is to be attributed to STD treatment, it is important to have a control group without an STD for which repeat measures are made.

It is worth noting that the included studies only reported the effect of STD treatment among patients who were successfully treated. Thus, we are unsure of what the effect of STD treatment on HIV is in an unselected group of STD patients treated with syndromic management in a developing country, for example. It may be that the absolute effect on overall HIV transmission is relatively small. This may be especially so if asymptomatic patients are targeted,8 but is less likely if symptomatic STD patients (who probably have a higher viral load due to greater inflammation) are targeted.7

Relatively poor follow-up procedures may be a feature of studies among sex workers and patients with STDs; however, Ghys et al14 reported a 70% follow-up rate, and Cohen et al11 reported an 86% rate. There was marked variation in the study population used in the included studies, ranging from sex workers to pregnant women, with correspondingly variable baseline levels of STD and HIV. Of more concern is the different HIV-detection methods used. DNA and RNA assays measure different factors, and we are careful not to overinterpret pooled data from studies that use different assays. It will be important for researchers to agree on a common standard assay. Diagnosis of chlamydial infection may be particularly difficult, and a wide range of diagnostic methods are used, making interpretation of results difficult. It was also difficult to interpret some data because not all studies reported results by infecting organism. It may be preferable to report by individual organism, by STD syndrome, and by number of patients with any STD, because this might allow some perspective to be gained on the impact of STD-treatment policies on HIV transmission.

For the future, a series of cohort studies including men and women who are recruited from a variety of settings, with high levels of follow up, and with repeat standardized measures performed in each group, and with adjustment for other risk factors for shedding would provide useful information regarding the relationship between STD and HIV and between STD treatment and HIV in genital secretions. Further, it will be useful to try to explore the relative importance of asymptomatic and symptomatic STD on HIV genital-tract shedding.

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