Risk of Human Immunodeficiency Virus Acquisition Among High-Risk Heterosexuals With Nonviral Sexually Transmitted Infections: A Systematic Review and Meta-Analysis

Abstract

Background: Nonviral sexually transmitted infections (STIs) increase risk of sexually acquired human immunodeficiency virus (HIV) infection. Updated risk estimates carefully scrutinizing temporality bias of studies are needed.

Methods: We conducted a systematic review (PROSPERO CRD42018084299) of peer-reviewed studies evaluating variation in risk of HIV infection among high-risk heterosexuals diagnosed with any of: Chlamydia trachomatis, Mycoplasma genitalium, Neisseria gonorrhoeae, Treponema pallidum, and/or Trichomonas vaginalis. We searched PubMed, Web of Science, and Embase databases through December 2017 and included studies where STIs and HIV were assessed using laboratory tests or medical examinations and where STI was diagnosed before HIV. After dual screening, data extraction, and risk of bias assessment, we meta-analytically pooled risk ratios (RRs).

Results: We found 32 eligible studies reporting k = 97 effect size estimates of HIV acquisition risk due to infection with one of the abovementioned STIs. Most data were based on women engaged in sex work or other high-risk occupations in developing countries. Many studies did not measure or adjust for known confounders, including drug injection and condom use, and most were at medium or high risk of bias because of the potential for undetected HIV infection to have occurred before STI infection. Human immunodeficiency virus acquisition risk increased among women infected with any pathogen; the effect was greatest for women infected with Mycoplasma genitalium (RR, 3.10; 95% confidence interval [CI], 1.63-5.92; k = 2) and gonorrhea (RR, 2.81; 95% CI, 2.25-3.50; k = 16) but also statistically significant for women infected with syphilis (RR, 1.67; 95% CI, 1.23-2.27; k = 17), trichomonas (RR, 1.54; 95% CI, 1.31-1.82; k = 17), and chlamydia (RR, 1.49; 95% CI, 1.08-2.04; k = 14). For men, data were space except for syphilis (RR, 1.77; 95% CI, 1.22-2.58; k = 5).

Conclusion: Nonviral STI increases risk of heterosexual HIV acquisition, although uncertainty remains because of risk of bias in primary studies.

Figure 1.. Identification and screening of bibliographic records for systematic review of the effect of nonviral STI diagnosis on the risk of HIV seroconversion among high-risk heterosexuals (search up to January 2018)

Figure 2.. Assessment of risk of bias for effect-size-level data (k=97) on the effect of nonviral sexually transmitted infection diagnosis on the risk of HIV acquisition among high-risk heterosexuals.

Figures 3a to 3d.. Forest plots for risk ratios for nonviral STI diagnosis and risk of HIV acquisition among female high-risk heterosexuals1

Figure 3a: RR for syphilis diagnosis and risk of HIV acquisition among female high-risk heterosexuals (k=17) Figure 3b: RR for trichomonas vaginalis diagnosis and risk of HIV acquisition among female high-risk heterosexuals (k-17) Figure 3c: RR for gonorrhea diagnosis and risk of HIV acquisition among female high-risk heterosexuals (k=16) Figure 3d: RR for chlamydia diagnosis and risk of HIV acquisition among female high-risk heterosexuals (k=14) ¹Where studies reported multiple effect sizes for the same population-pathogen pairing, estimates and sensitivity analysis (SA) risk ratio (RR) ranges above reflect higher-quality data (i.e., multivariate-adjusted vs unadjusted and/or shorter duration of follow-up). SA RR ranges for lower-quality data are reported in footnotes. ²Syphilis-high-risk occupation SA RR range: 1.40–1.83. Removing the following studies changed RR ≥0.05: Auvert 2011: 1.67 (1.19, 2.34); Braunstein 2011: 1.45 (1.09, 1.94); Ghys 2001: 1.65 (1.15, 2.37); Plummer 1991: 1.83 (1.32, 2.56); Riedner 2006: 1.52 (1.07, 2.15); Su 2016: 1.40 (1.05, 1.87); Watson-Jones 2009: 1.68 (1.20, 2.36). RR when lower-quality effect size was substituted from Braunstein 2011 was 1.42 (1.09, 1.84); when substituted from Vandepitte 2013 was 1.54 (1.16, 2.06) ³Syphilis overall SA RR range: 1.56–1.82^. Removing the following studies changed RR ≥0.05: Auvert 2011: 1.74 (1.27, 2.39); Braunstein 2011: 1.58 (1.18, 2.13); Ghys 2001: 1.73 (1.25, 2.39); Hanson 2005: 1.56 (1.17, 2.07); Metha 2006: 1.61 (1.18, 2.20); Plummer 1991: 1.81 (1.29, 2.54); Su 2016: 1.57 (1.16, 2.13); Wall 2017: 1.82 (1.30, 2.54); Watson-Jones 2009: 1.75 (1.28, 2.40). RR when lower-quality effect size was substituted for Braunstein 2011 was 1.58 (1.19, 2.10). ⁴Trichomoniasis high-risk occupation SA RR range: 1.44–1.53. RR when lower-quality effect size was substituted from Braunstein 2011 was 1.44 (1.21, 1.72). ⁵Trichomoniasis overall SA RR range: 1.48–1.58. ⁶Gonorrhea high-risk occupation SA RR range: 2.60–3.13.^. Removing the following studies changed RR ≥0.05: Ghys 2001: 2.71 (2.16, 3.41); Kaul 2004: 2.77 (2.19, 3.51); Laga 1993: 2.75 (2.12, 3.56); Martin 1998: 2.97 (2.37, 3.72); Masese 2015: 3.13 (2.45, 4.00); Ramjee 2005: 2.94 (2.30, 3.76); Vandepitte 2013: 2.60 (2.09, 3.23). RR when lower-quality effect size was substituted from Vandepitte 2013 was 2.61 (2.11, 3.24). ⁷Gonorrhea overall SA RR range: 2.58–3.05. Removing the following studies changed RR ≥0.05: Ghys 2001: 2.69 (2.16, 3.35); Kaul 2004: 2.74 (2.19, 3.43); Laga 1993: 2.71 (2.12, 3.46); Martin 1998: 2.94 (2.36, 3.67); Masese 2015: 3.05 (2.42, 3.84); Ramjee 2005: 2.89 (2.29, 3.65); Vandepitte 2013: 2.58 (2.1, 3.18). RR when lower-quality effect size was substituted from Vandepitte 2013 was 2.62 (2.15, 3.19). ⁸Chlamydia high-risk occupation SA RR range: 1.37–1.70. Removing the following studies changed RR ≥0.05: Auvert 2011 1.70 (1.31, 2.21); Kaul 2004: 1.40 (0.98, 2.00); Laga 1993: 1.37 (0.94, 2.02); Nagot 2005: 1.69 (1.24, 2.29); Plummer 1991: 1.44 (0.95, 2.17); Vandepitte 2013: 1.43 (0.97, 2.1); Watson-Jones 2009: 1.38 (0.96, 2.00). ⁹Chlamydia overall SA RR range: 1.37, 1.69. Removing the following studies changed RR ≥0.05: Auvert 2011: 1.68 (1.29, 2.17); Kaul 2004: 1.41 (1.02, 1.95); Laga 1993: 1.37 (0.97, 1.94); Nagot 2005: 1.69 (1.28, 2.22); Plummer 1991: 1.43 (0.98, 2.08); Vandepitte 2013: 1.42 (1.00, 2.02); Watson-Jones 2009: 1.39 (0.99, 1.94). RR when lower-quality effect size was substituted from Kapiga 2007 was 1.60 (1.12, 2.29).

Figures 3a to 3d.. Forest plots for risk ratios for nonviral STI diagnosis and risk of HIV acquisition among female high-risk heterosexuals1

Figure 3a: RR for syphilis diagnosis and risk of HIV acquisition among female high-risk heterosexuals (k=17) Figure 3b: RR for trichomonas vaginalis diagnosis and risk of HIV acquisition among female high-risk heterosexuals (k-17) Figure 3c: RR for gonorrhea diagnosis and risk of HIV acquisition among female high-risk heterosexuals (k=16) Figure 3d: RR for chlamydia diagnosis and risk of HIV acquisition among female high-risk heterosexuals (k=14) ¹Where studies reported multiple effect sizes for the same population-pathogen pairing, estimates and sensitivity analysis (SA) risk ratio (RR) ranges above reflect higher-quality data (i.e., multivariate-adjusted vs unadjusted and/or shorter duration of follow-up). SA RR ranges for lower-quality data are reported in footnotes. ²Syphilis-high-risk occupation SA RR range: 1.40–1.83. Removing the following studies changed RR ≥0.05: Auvert 2011: 1.67 (1.19, 2.34); Braunstein 2011: 1.45 (1.09, 1.94); Ghys 2001: 1.65 (1.15, 2.37); Plummer 1991: 1.83 (1.32, 2.56); Riedner 2006: 1.52 (1.07, 2.15); Su 2016: 1.40 (1.05, 1.87); Watson-Jones 2009: 1.68 (1.20, 2.36). RR when lower-quality effect size was substituted from Braunstein 2011 was 1.42 (1.09, 1.84); when substituted from Vandepitte 2013 was 1.54 (1.16, 2.06) ³Syphilis overall SA RR range: 1.56–1.82^. Removing the following studies changed RR ≥0.05: Auvert 2011: 1.74 (1.27, 2.39); Braunstein 2011: 1.58 (1.18, 2.13); Ghys 2001: 1.73 (1.25, 2.39); Hanson 2005: 1.56 (1.17, 2.07); Metha 2006: 1.61 (1.18, 2.20); Plummer 1991: 1.81 (1.29, 2.54); Su 2016: 1.57 (1.16, 2.13); Wall 2017: 1.82 (1.30, 2.54); Watson-Jones 2009: 1.75 (1.28, 2.40). RR when lower-quality effect size was substituted for Braunstein 2011 was 1.58 (1.19, 2.10). ⁴Trichomoniasis high-risk occupation SA RR range: 1.44–1.53. RR when lower-quality effect size was substituted from Braunstein 2011 was 1.44 (1.21, 1.72). ⁵Trichomoniasis overall SA RR range: 1.48–1.58. ⁶Gonorrhea high-risk occupation SA RR range: 2.60–3.13.^. Removing the following studies changed RR ≥0.05: Ghys 2001: 2.71 (2.16, 3.41); Kaul 2004: 2.77 (2.19, 3.51); Laga 1993: 2.75 (2.12, 3.56); Martin 1998: 2.97 (2.37, 3.72); Masese 2015: 3.13 (2.45, 4.00); Ramjee 2005: 2.94 (2.30, 3.76); Vandepitte 2013: 2.60 (2.09, 3.23). RR when lower-quality effect size was substituted from Vandepitte 2013 was 2.61 (2.11, 3.24). ⁷Gonorrhea overall SA RR range: 2.58–3.05. Removing the following studies changed RR ≥0.05: Ghys 2001: 2.69 (2.16, 3.35); Kaul 2004: 2.74 (2.19, 3.43); Laga 1993: 2.71 (2.12, 3.46); Martin 1998: 2.94 (2.36, 3.67); Masese 2015: 3.05 (2.42, 3.84); Ramjee 2005: 2.89 (2.29, 3.65); Vandepitte 2013: 2.58 (2.1, 3.18). RR when lower-quality effect size was substituted from Vandepitte 2013 was 2.62 (2.15, 3.19). ⁸Chlamydia high-risk occupation SA RR range: 1.37–1.70. Removing the following studies changed RR ≥0.05: Auvert 2011 1.70 (1.31, 2.21); Kaul 2004: 1.40 (0.98, 2.00); Laga 1993: 1.37 (0.94, 2.02); Nagot 2005: 1.69 (1.24, 2.29); Plummer 1991: 1.44 (0.95, 2.17); Vandepitte 2013: 1.43 (0.97, 2.1); Watson-Jones 2009: 1.38 (0.96, 2.00). ⁹Chlamydia overall SA RR range: 1.37, 1.69. Removing the following studies changed RR ≥0.05: Auvert 2011: 1.68 (1.29, 2.17); Kaul 2004: 1.41 (1.02, 1.95); Laga 1993: 1.37 (0.97, 1.94); Nagot 2005: 1.69 (1.28, 2.22); Plummer 1991: 1.43 (0.98, 2.08); Vandepitte 2013: 1.42 (1.00, 2.02); Watson-Jones 2009: 1.39 (0.99, 1.94). RR when lower-quality effect size was substituted from Kapiga 2007 was 1.60 (1.12, 2.29).

Figures 3a to 3d.. Forest plots for risk ratios for nonviral STI diagnosis and risk of HIV acquisition among female high-risk heterosexuals1

Figure 3a: RR for syphilis diagnosis and risk of HIV acquisition among female high-risk heterosexuals (k=17) Figure 3b: RR for trichomonas vaginalis diagnosis and risk of HIV acquisition among female high-risk heterosexuals (k-17) Figure 3c: RR for gonorrhea diagnosis and risk of HIV acquisition among female high-risk heterosexuals (k=16) Figure 3d: RR for chlamydia diagnosis and risk of HIV acquisition among female high-risk heterosexuals (k=14) ¹Where studies reported multiple effect sizes for the same population-pathogen pairing, estimates and sensitivity analysis (SA) risk ratio (RR) ranges above reflect higher-quality data (i.e., multivariate-adjusted vs unadjusted and/or shorter duration of follow-up). SA RR ranges for lower-quality data are reported in footnotes. ²Syphilis-high-risk occupation SA RR range: 1.40–1.83. Removing the following studies changed RR ≥0.05: Auvert 2011: 1.67 (1.19, 2.34); Braunstein 2011: 1.45 (1.09, 1.94); Ghys 2001: 1.65 (1.15, 2.37); Plummer 1991: 1.83 (1.32, 2.56); Riedner 2006: 1.52 (1.07, 2.15); Su 2016: 1.40 (1.05, 1.87); Watson-Jones 2009: 1.68 (1.20, 2.36). RR when lower-quality effect size was substituted from Braunstein 2011 was 1.42 (1.09, 1.84); when substituted from Vandepitte 2013 was 1.54 (1.16, 2.06) ³Syphilis overall SA RR range: 1.56–1.82^. Removing the following studies changed RR ≥0.05: Auvert 2011: 1.74 (1.27, 2.39); Braunstein 2011: 1.58 (1.18, 2.13); Ghys 2001: 1.73 (1.25, 2.39); Hanson 2005: 1.56 (1.17, 2.07); Metha 2006: 1.61 (1.18, 2.20); Plummer 1991: 1.81 (1.29, 2.54); Su 2016: 1.57 (1.16, 2.13); Wall 2017: 1.82 (1.30, 2.54); Watson-Jones 2009: 1.75 (1.28, 2.40). RR when lower-quality effect size was substituted for Braunstein 2011 was 1.58 (1.19, 2.10). ⁴Trichomoniasis high-risk occupation SA RR range: 1.44–1.53. RR when lower-quality effect size was substituted from Braunstein 2011 was 1.44 (1.21, 1.72). ⁵Trichomoniasis overall SA RR range: 1.48–1.58. ⁶Gonorrhea high-risk occupation SA RR range: 2.60–3.13.^. Removing the following studies changed RR ≥0.05: Ghys 2001: 2.71 (2.16, 3.41); Kaul 2004: 2.77 (2.19, 3.51); Laga 1993: 2.75 (2.12, 3.56); Martin 1998: 2.97 (2.37, 3.72); Masese 2015: 3.13 (2.45, 4.00); Ramjee 2005: 2.94 (2.30, 3.76); Vandepitte 2013: 2.60 (2.09, 3.23). RR when lower-quality effect size was substituted from Vandepitte 2013 was 2.61 (2.11, 3.24). ⁷Gonorrhea overall SA RR range: 2.58–3.05. Removing the following studies changed RR ≥0.05: Ghys 2001: 2.69 (2.16, 3.35); Kaul 2004: 2.74 (2.19, 3.43); Laga 1993: 2.71 (2.12, 3.46); Martin 1998: 2.94 (2.36, 3.67); Masese 2015: 3.05 (2.42, 3.84); Ramjee 2005: 2.89 (2.29, 3.65); Vandepitte 2013: 2.58 (2.1, 3.18). RR when lower-quality effect size was substituted from Vandepitte 2013 was 2.62 (2.15, 3.19). ⁸Chlamydia high-risk occupation SA RR range: 1.37–1.70. Removing the following studies changed RR ≥0.05: Auvert 2011 1.70 (1.31, 2.21); Kaul 2004: 1.40 (0.98, 2.00); Laga 1993: 1.37 (0.94, 2.02); Nagot 2005: 1.69 (1.24, 2.29); Plummer 1991: 1.44 (0.95, 2.17); Vandepitte 2013: 1.43 (0.97, 2.1); Watson-Jones 2009: 1.38 (0.96, 2.00). ⁹Chlamydia overall SA RR range: 1.37, 1.69. Removing the following studies changed RR ≥0.05: Auvert 2011: 1.68 (1.29, 2.17); Kaul 2004: 1.41 (1.02, 1.95); Laga 1993: 1.37 (0.97, 1.94); Nagot 2005: 1.69 (1.28, 2.22); Plummer 1991: 1.43 (0.98, 2.08); Vandepitte 2013: 1.42 (1.00, 2.02); Watson-Jones 2009: 1.39 (0.99, 1.94). RR when lower-quality effect size was substituted from Kapiga 2007 was 1.60 (1.12, 2.29).

Figures 3a to 3d.. Forest plots for risk ratios for nonviral STI diagnosis and risk of HIV acquisition among female high-risk heterosexuals1

Figure 3a: RR for syphilis diagnosis and risk of HIV acquisition among female high-risk heterosexuals (k=17) Figure 3b: RR for trichomonas vaginalis diagnosis and risk of HIV acquisition among female high-risk heterosexuals (k-17) Figure 3c: RR for gonorrhea diagnosis and risk of HIV acquisition among female high-risk heterosexuals (k=16) Figure 3d: RR for chlamydia diagnosis and risk of HIV acquisition among female high-risk heterosexuals (k=14) ¹Where studies reported multiple effect sizes for the same population-pathogen pairing, estimates and sensitivity analysis (SA) risk ratio (RR) ranges above reflect higher-quality data (i.e., multivariate-adjusted vs unadjusted and/or shorter duration of follow-up). SA RR ranges for lower-quality data are reported in footnotes. ²Syphilis-high-risk occupation SA RR range: 1.40–1.83. Removing the following studies changed RR ≥0.05: Auvert 2011: 1.67 (1.19, 2.34); Braunstein 2011: 1.45 (1.09, 1.94); Ghys 2001: 1.65 (1.15, 2.37); Plummer 1991: 1.83 (1.32, 2.56); Riedner 2006: 1.52 (1.07, 2.15); Su 2016: 1.40 (1.05, 1.87); Watson-Jones 2009: 1.68 (1.20, 2.36). RR when lower-quality effect size was substituted from Braunstein 2011 was 1.42 (1.09, 1.84); when substituted from Vandepitte 2013 was 1.54 (1.16, 2.06) ³Syphilis overall SA RR range: 1.56–1.82^. Removing the following studies changed RR ≥0.05: Auvert 2011: 1.74 (1.27, 2.39); Braunstein 2011: 1.58 (1.18, 2.13); Ghys 2001: 1.73 (1.25, 2.39); Hanson 2005: 1.56 (1.17, 2.07); Metha 2006: 1.61 (1.18, 2.20); Plummer 1991: 1.81 (1.29, 2.54); Su 2016: 1.57 (1.16, 2.13); Wall 2017: 1.82 (1.30, 2.54); Watson-Jones 2009: 1.75 (1.28, 2.40). RR when lower-quality effect size was substituted for Braunstein 2011 was 1.58 (1.19, 2.10). ⁴Trichomoniasis high-risk occupation SA RR range: 1.44–1.53. RR when lower-quality effect size was substituted from Braunstein 2011 was 1.44 (1.21, 1.72). ⁵Trichomoniasis overall SA RR range: 1.48–1.58. ⁶Gonorrhea high-risk occupation SA RR range: 2.60–3.13.^. Removing the following studies changed RR ≥0.05: Ghys 2001: 2.71 (2.16, 3.41); Kaul 2004: 2.77 (2.19, 3.51); Laga 1993: 2.75 (2.12, 3.56); Martin 1998: 2.97 (2.37, 3.72); Masese 2015: 3.13 (2.45, 4.00); Ramjee 2005: 2.94 (2.30, 3.76); Vandepitte 2013: 2.60 (2.09, 3.23). RR when lower-quality effect size was substituted from Vandepitte 2013 was 2.61 (2.11, 3.24). ⁷Gonorrhea overall SA RR range: 2.58–3.05. Removing the following studies changed RR ≥0.05: Ghys 2001: 2.69 (2.16, 3.35); Kaul 2004: 2.74 (2.19, 3.43); Laga 1993: 2.71 (2.12, 3.46); Martin 1998: 2.94 (2.36, 3.67); Masese 2015: 3.05 (2.42, 3.84); Ramjee 2005: 2.89 (2.29, 3.65); Vandepitte 2013: 2.58 (2.1, 3.18). RR when lower-quality effect size was substituted from Vandepitte 2013 was 2.62 (2.15, 3.19). ⁸Chlamydia high-risk occupation SA RR range: 1.37–1.70. Removing the following studies changed RR ≥0.05: Auvert 2011 1.70 (1.31, 2.21); Kaul 2004: 1.40 (0.98, 2.00); Laga 1993: 1.37 (0.94, 2.02); Nagot 2005: 1.69 (1.24, 2.29); Plummer 1991: 1.44 (0.95, 2.17); Vandepitte 2013: 1.43 (0.97, 2.1); Watson-Jones 2009: 1.38 (0.96, 2.00). ⁹Chlamydia overall SA RR range: 1.37, 1.69. Removing the following studies changed RR ≥0.05: Auvert 2011: 1.68 (1.29, 2.17); Kaul 2004: 1.41 (1.02, 1.95); Laga 1993: 1.37 (0.97, 1.94); Nagot 2005: 1.69 (1.28, 2.22); Plummer 1991: 1.43 (0.98, 2.08); Vandepitte 2013: 1.42 (1.00, 2.02); Watson-Jones 2009: 1.39 (0.99, 1.94). RR when lower-quality effect size was substituted from Kapiga 2007 was 1.60 (1.12, 2.29).