Research on Sexually Transmitted Diseases

In a nutshell

  • What is the problem? Hundreds of millions of people are infected with sexually transmitted diseases (STDs), and more than a hundred thousand die due to STDs other than HIV each year. The World Health Organization (WHO) and Global Burden of Disease (GBD) Study estimate that STDs other than HIV and HPV are responsible for approximately 9-13 million disability-adjusted life years (DALYs) per year. Based on their impact and the availability of treatments and preventative measures, we chose three diseases to investigate in more detail: herpes simplex virus (HSV), syphilis, and human papillomavirus (HPV). The GBD estimated the burden of HSV at approximately 300k DALYs per year, but this estimate does not include the burden of some additional conditions caused by HSV. We briefly looked at the burden of these conditions and concluded that the true burden may be somewhat or substantially larger. HSV cannot be cured and there is no vaccine, although antivirals can be used to treat it. Syphilis is responsible for most of the direct burden of STDs (7-11 million DALYs per year, according to the WHO and GBD), and there is no vaccine, but it can be cured with antibiotics. HPV is a necessary cause of cervical cancer, which is estimated to cause approximately 7-9 million DALYs per year, and can contribute to the development of other cancers as well (the burden of HPV is not included in WHO and GBD assessments of the burden of STDs, but cervical cancer burden is included separately in these sources). There are vaccines that appear to confer immunity against some strains of HPV, and precancerous lesions can often be removed once detected, but HPV cannot be cured.
  • Who else is working on it? It’s our impression that there is relatively little nonprofit involvement in and private funding for STD research and development. The NIH contributed approximately $250 million in funding to support STD research in 2015 (funding for HIV and HPV research and development categorized separately from the $250 million figure). Grantome searches suggest NIH and NSF funding of approximately $100 million, $150 million, and $20 million in funding for HSV, HPV, and syphilis research in 2013, respectively.


Published: October 2016

What is the problem?

Sexually transmitted diseases (STDs) are widespread. Hundreds of millions of people are infected with at least one STD,1 and the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimated that STDs other than HIV and HPV caused approximately 142,000 deaths in 2013, while HIV caused approximately 1,341,000 deaths in 2013.2

We may conduct a separate investigation into HIV/AIDS at a later date, but did not include it in this investigation.

We believe it is widely accepted that mother-to-child STD transmission can result in stillbirths, infant mortality, and chronic health conditions. Stigma, fear, and avoidance of sexual intimacy associated with STDs may lower quality of life. Common STDs, including genital herpes, HPV, and syphilis, are associated with an increased risk of HIV transmission, but it appears that high-quality evidence of a causal relationship is scarce. (See below for our take on this.)

Vaccines are available to prevent HPV (although note that currently-available HPV vaccines do not protect against all strains of HPV3) and hepatitis B.4 Other STDs, including syphilis, chlamydia, and trichomoniasis, are treatable and generally curable with antibiotics,5 although some STDs, especially gonorrhea, are developing resistance to antibiotics.6

We formulated an initial list of STDs from several other lists of STDs that we found.7 We declined to include infections such as Pelvic Inflammatory Disease (PID) that result from infection with other STDs. Of these, we initially decided to assess the impact of and funding for diseases that are predominantly sexually-transmitted other than HIV, and that are currently difficult or impossible to treat or cure because we thought it was more likely that additional scientific research would be beneficial for cases where reliable cures or treatments have not been found. We later decided to investigate predominantly sexually-transmitted diseases that had a reported impact of greater than five million disability-adjusted life years (DALYs) per year as well, regardless of whether treatments or cures for those are available.8 Based on these processes, we decided to examine herpes simplex virus (HSV), syphilis, and human papillomavirus (HPV) in more detail.

Size of the problem

Overall burden

To get a sense of the impact of different STDs on public health, we looked at the most recent estimates of the global annual burden of major STDs (excluding HIV and HPV) in DALYs from the Global Burden of Disease Study (GBD) and the World Health Organization’s (WHO) Global Health Observatory (GHO). The results are below:

Disease Global Burden of Disease (2013) World Health Organization (2012)
Syphilis 11,324,500 7,038,630
Chlamydial infections/Chlamydia 692,400 1,429,973
Gonococcal infections/Gonorrhea 313,900 545,145
Genital herpes 311,600 NA
Trichomoniasis 113,900 172,850
Other STDs 101,000 734,0759
Total burden of STDs (excluding HIV) in DALYs 12,857,200 9,920,672

However, it’s our impression that these numbers are very uncertain (indeed, they are not in close agreement with one another). The estimates did not include the impacts of neonatal forms of some STDs, and may have missed other impacts as well.10

Additionally, we note that there are major negative impacts of STDs that we do not quantitatively assess in this report, such as the psychological and sociological effects of the presence of STDs in a community (e.g. fear of transmission and stigmatization). In addition, there may be impacts we do not know of and that our brief investigation did not uncover.

STDs and HIV Transmission

There is evidence of a correlation between HIV and infection with other STDs, including HSV, HPV, and gonorrhea.11 Some researchers also believe there are plausible mechanisms by which the presence of other STDs could increase the likelihood of HIV transmission, namely by 1) increasing the incidence of lesioned regions of flesh around the genitals, and 2) recruiting cells carrying CD4 receptors (which HIV uses to gain entry into host T-cells) to the area.12 However, we believe the ability to definitively determine a causal relationship is complicated by confounding variables (for example, behavioral and health-status factors that contribute to the risk of contracting one STD may increase the risk of contracting another), and limitations on the types of experiments that can be performed without harming participants. We are not confident that attempts to fully control for confounding variables are able to do so.

We know of two small RCTs which concluded that HSV antivirals reduced HIV levels, either in the seminal fluids or in plasma and around the cervix.13 However, according to Mayer and Venkatesh 2011, in a meta-analysis of randomized controlled trials (RCTs) on interventions to distribute antivirals for HSV and antibiotics for bacterial STDs, six out of seven RCTs they examined did not find a statistically-significant reduction in HIV transmission, nor have studies in subsequent reviews (note that there is overlap between the studies included in the different reviews).14 Given that the majority of studies we encountered did not find an effect of STD treatment and prevention on HIV transmission, we chose not to include a quantitative estimate of the potential impact of STDs on HIV. However, we note that if STDs are in fact responsible for a substantial proportion of HIV transmission, that might make their overall impact substantially larger than our estimates below.15

Some studies have detected an association between HIV and HPV.16 Additionally, mechanisms by which HPV infection could increase HIV transmission have been proposed.17 However, it is our impression that as of 2015, no RCTs have been conducted on the impact of HPV vaccination on HIV transmission.18

We do not know if vaccines or improved treatments for STDs would reduce HIV transmission, or whether increased access to currently-available STD treatments would help prevent HIV.

Genital herpes

The herpes simplex virus (HSV) occurs in two forms, HSV-1 and HSV-2.19 Hundreds of millions of people are infected with one or both types of HSV, although many show no symptoms.20 Both types can be transmitted by sex.21 There is no commercially-available HSV vaccine and HSV infections cannot be cured, but antiviral agents can reduce outbreaks.22

Major sources of disease burden from HSV include:

Genital ulcers: The Global Burden of Disease reports that genital HSV resulted in 311,600 years lived with disability (YLD) in 2013 due to genital ulcer disease.23 We have not vetted this estimate, but did attempt to independently derive it by assigning what we felt was a plausible disability weight to genital ulcers and multiplying by its prevalence, and found that it was within the range of what we expected.

Neonatal deaths from HSV: We found it difficult to come to an understanding the impact of neonatal HSV. This is because:

  • We have major uncertainty about current global neonatal herpes incidence, although the data we found suggest that the overall incidence was likely more than 1/100,000 and less than 1/100 in the late 1990s and early 2000s.24
  • We are highly uncertain about the neonatal herpes mortality rate, and the sources we’ve found have not given us a strong sense of the likely true number because the estimates vary somewhat. We haven’t investigated their methodology, and we are unsure of how the mortality rate varies by country.25 We don’t know if the difference in estimates of the mortality rates stem primarily from differences in incidence at the different study sites and times, differences in proportion of cases treated, differences in the quality of the treatment, other factors, or some combination of these. We think it require substantial additional work to understand neonatal HSV mortality rates somewhat better, but that even if we put in more time, we might not gain clarity on this.
  • We did not look into the number of infants that sustain lifelong sources of disability from neonatal HSV.

Given the number of births/year,26 it seems likely to us that thousands or tens of thousands of infants are infected with HSV every year, and it seems possible to us that more than 10% of those infants die. If that were true, the impact of neonatal HSV might represent a substantial fraction or the majority of the total burden of HSV.27

Severe vision impairment from HSV: One source suggests that 40,000 people per year may become profoundly visually impaired in one or both eyes due to HSV keratitis (an inflammation of the cornea).28 We did not vet this estimate, and are not confident that these numbers reflect the true burden of severe vision impairment from HSV. We don’t know how many DALYs HSV keratitis is likely responsible for. It’s our impression that most cases of HSV keratitis occur late in life but may be more severe in children. 29

In many cases, HSV vision impairment may be the result of HSV-1 that was not directly sexually transmitted. Many researchers believe that HSV-1 can be and often is transmitted by non-sexual kissing (for example by family members) or by sharing items that touch the mouth such as eating utensils and toothbrushes.

Other impacts: We did not investigate several other impacts of HSV, including:

  • Sequelae in non-fatal cases of neonatal HSV
  • Cases of mildly-moderately impaired vision from HSV
  • Oral HSV ulcers
  • A proposed connection between HSV-1 infection and the development of Alzheimer’s Disease30
  • Encephalitis and meningitis from herpes31
  • Herpes whitlow and gladiatorum32

Overall burden: The GBD estimated that genital herpes resulted in approximately 300k DALYs in 2013. Based on our research into conditions caused by HSV but not included in the GBD estimate (namely, the unquantified but possibly-substantial impact of HSV keratitis and neonatal HSV, the possible and (if real) plausibly substantial impact of HSV on HIV/AIDs transmission and Alzheimer’s Disease, and the likely small impact of the other conditions above) we would guess that the true impact of HSV is substantially larger, although we don’t know how much larger.

Human papillomavirus

HPV is a common infection; the WHO estimates that approximately 12% of women with normal cytological findings (which we believe to mean no cellular signs indicating cervical cancer or precancerous changes in the cervix, indicating that this number is likely an underestimate of the proportion of women with HPV) and 21% of men worldwide are infected at a given time.33 There are many strains of HPV, most of which are asymptomatic but some of which increase cancer risk around the infected area (especially the cervix) or cause genital warts.34

There is no treatment we know of for HPV, but there are vaccines that confer protection against some strains of the virus.35 All the vaccines protect against strains 16 and 18,36 which, according to the National Cancer Institute, are together responsible for 70% of cervical cancers.37

There are also procedures that allow healthcare workers to identify and, if necessary, remove precancerous lesions on the cervix.38 According to the WHO, HPV infections of healthy individuals often spontaneously resolve themselves within two years39 and it usually takes approximately ten years for HPV infection to progress to an invasive cancer.40

Major sources of disease burden from HPV include:

Cervical cancer: In 2012 it was reported that there were 528,000 cases of cervical cancer and 266,000 deaths from cervical cancer,41 all the result of some strain of HPV.42 The DALY burden of cervical cancer was estimated at 6.9M in 2013 by the GBD,43 and 9.2M by the WHO in 2012.44

Cancers of the vulva, vagina, penis, anus, mouth, and oropharynx attributable to HPV:

There is evidence linking HPV to cancers of the vulva, vagina, penis, anus, mouth, and oropharynx.45

One source indicated that in 2006, 87.8% of cancers from HPV were cervical cancers.46 so we believe that the estimate of the burden of cervical cancer captures the majority of the known direct harm from HPV.

Other impacts: There are other impacts of HPV which are not included in our calculation of the burden of HPV. These include:

  • Respiratory papillomatosis47
  • A possible association between lung cancer and HPV. It’s our impression that a causal link has not been established, and we are uncertain about the quality of the evidence for the connection.48
  • Genital warts
  • Common skin warts and rare skin conditions in immunocompromised individuals.49 However, it is our understanding that these result from strains of HPV that are not predominantly sexually transmitted.

Some research suggests that HPV vaccination may increase the risk of becoming infected with the strains that the vaccine does not protect against.50 We have not fully investigated this claim, and do not know how much it detracts from the public health benefit of HPV vaccines, if at all.

Overall burden: In summary-

  • The GBD estimates the burden of cervical cancer at 6.9M DALYs
  • The WHO estimates the burden of cervical cancer at 9.2M DALYs
  • HPV can cause other cancers as well, but these cancers probably contribute a small proportion of the total burden.
  • There is evidence of an associated between HPV infection and HIV transmission, but we are unsure about the strength and cause of this association.
  • We have not included other health consequences of HPV, which we believe to be small in comparison.

Syphilis

Syphilis is a bacterial infection caused by the bacterium Treponema pallidum.51 When left untreated, it can lead to sores, rashes, eye problems, neurological and heart problems, and death.52 It can be treated and the infection cured with antibiotics.53

Overall burden: In 2013 the GBD estimated that there were 136,848 deaths due to syphilis, of which 120,537 were in children five years of age or under,54 while the WHO GHO estimated that there were 78,910 deaths from syphilis in 2012, of which 67,489 were in children five years of age or under.55 The DALY burden from syphilis (including neonatal syphilis) was estimated by the GBD at 11.3M DALYs and the WHO GHO at 7.0M DALYs.56 Potential effects of syphilis on HIV transmission were not included in these assessments,57 but we do not know of other direct impacts of syphilis that may have been excluded (despite a brief search).

Who else is working on this?

We do not have a comprehensive understanding of which organizations fund research on STDs, as opposed to raising awareness, offering services, or advocating on behalf of individuals that suffer from STDs.58 However, it’s our understanding that philanthropic and nonprofit involvement in STD research is minimal. We are not aware of non-profit organizations specifically supporting HSV or syphilis research.

How much funding is in this area?

Total

The total NIH funding for sexually transmitted diseases/herpes (not including funding for HIV/AIDS, any hepatitis virus, or HPV/cervical cancer vaccines) was approximately $250M in 2015.59 It was our impression of NIH STD funding that there is substantial funding for HPV vaccine trials, testing the effects of the HPV vaccine, and cervical cancer diagnostics. Even though HIV/AIDS had its own section, there seemed to be some funding allocated for HIV/AIDS research listed in the “sexually transmitted diseases/herpes” section, some funding for social science programs on sexual health and safety, and research on HSV and HSV vaccine candidates. We saw several funded projects on potential chlamydia and gonorrhea vaccine candidates.60 In addition, we identified approximately $1.4M in funding for STDs from private foundations in 2012.61

We searched Grantome.com, a database of scientific research grants, for information about grants that included the words “sexually transmitted,” and found that in 2013 there was $188M in funding reported that met these search criteria.62

We looked into the assets and funding from other sources, including smaller sources and those predominantly dedicated to STD advocacy, awareness-building, and service provision rather than research and development, but these numbers did not significantly affect our view of the crowdedness of this space.63

The funding for research and development for each of our STDs of interest is below.

HSV

  • Grantome, 2013, approximate: $104.3M64
  • NIH Project Reporter, 2015, approximate: $5.8-137.9M65

HPV

  • Grantome, 2013, approximate: $147.6M66
  • NIH, Estimates for Funding of Varion Research, Condition, and Disease Categories, 2015: $31M67
  • NIH Project Reporter, 2015, approximate: $35.2-204.3M68

Syphilis

  • Grantome, 2013, approximate: $17.3M69
  • NIH Project Reporter, 2015, approximate: : $2.2-22.9M70

Our process

We initially decided to investigate this area because we thought STD research might be impactful and neglected due to associated stigma. We focused on quickly determining this, without investigating potential interventions in this space. The specific steps we took to investigate importance and neglectedness are as follows.

For investigating importance, we:

  • Looked at global DALY burden from each STD in the GBD 2013 and WHO GHO 2012 data.
  • Attempted to independently derive DALY estimates, where possible, from lives lost.
  • Briefly researched the diseases we focused on, their sequelae, and treatments. We did this by reading fact sheets and Wikipedia articles about the diseases in question, scanning for highly-cited recent articles in Google Scholar about them, and investigating further points that seemed important.
  • Looked for relevant Cochrane Library articles on HPV, HSV, syphilis, and STDs in general.

For investigating neglectedness, we:

Questions for further investigation

Our investigation so far has focused almost exclusively on the burden of these diseases and how much attention they receive from funders of scientific research. If we were to do further research here, our primary focus would be on the tractability of potential research directions. Some questions we might aim to address include:

  • What are the greatest barriers to STD diagnosis? Would improved diagnostics for STD infections lead to higher rates of treatment and cure?
  • What are the greatest barriers to the development of new vaccines for STDs, including syphilis?
  • Would it be practical to deliver a syphilis vaccine to the required population?
  • How do HPV vaccines affect the prevalence and transmission of HPV strains against which they do not confer immunity? How is this likely to impact the future burden of HPV?
  • To what extent do STDs increase HIV transmission? To what extent do STD treatments and vaccines reduce HIV transmission, if at all?
  • What other research and development projects could potentially decrease the burden of STDs?
Document Source
990 Finder American Sexually Transmitted Diseases Association Form 990 2014 Source
990 Finder National Coalition of STD Directors Form 990 2013 Source
990 Finder The Foundation for Research into Sexually Transmitted Diseases Form 990 2013 Source
990 Finder: HPV and Anal Cancer Foundation Form 990 2013 Source
Baeten et al. 2008 Source
CDC Office of Financial Resources 2015 Annual Report Source
CDC: HPV Vaccine Information for Clinicians Source
CIA World Factbook Source
Clinuvel: Herpes Simplex Virus Source
Cochrane Library Source
Corey and Wald 2009 Source
Farazmand Woolley and Kinghorn 2011 Source
Farooq and Shukla 2012 Source
FDA News Release: Gardasil 9 Source
Foundation giving based on Foundation Center data Source
GBD 2013 DALYs from all causes Source
GBD 2013 deaths from syphilis Source
GBD 2013 International Classification of Diseases codes mapped to the Global Burden of Disease cause list Source
Genital Herpes - CDC Fact Sheet (Detailed) Source
GiveWell: DALY Source
Global Burden of Disease 2013: Mortality and Causes of Death Source
Global Burden of Disease Study 2013 (GBD 2013) Data Downloads - Full Results Source
Globocan Cervical Cancer Fact Sheet Source
Grantome.com Source
Grantome.com “herpes simplex” Source
Grantome.com “hpv” Source
Grantome.com “sexually transmitted” Source
Grantome.com “syphilis” Source
Guo et al. 2015 Source
Head et al. 2015 Source
Houlihan et al. 2012 Source
Human papillomavirus vaccines: WHO position paper, October 2014 Source
ICD 10 Data: Anogenital herpes Source
Johnston, Gottlieb, and Wald 2016 Source
Looker et al. 2015 Source
Looker Garnett and Schmid 2008 Source
Mayer and Venkatesh 2011 Source
Morris et al. 2008 Source
Mutua, M’Imunya, and Wiysonge 2012 Source
National Cancer Institute: HPV Vaccine Fact Sheet Source
Ng et al. 2011 Source
NIH 2015 STD/Herpes project listing Source
NIH Estimates of Funding for Various Research, Condition, and Disease Categories (RCDC) Source
NIH Project Reporter Source
NIH Reporter- Herpes simplex funding, project titles only Source
NIH Reporter- Herpes simplex funding, project titles, terms, and abstracts Source
NIH Reporter- HPV funding, project titles only Source
NIH Reporter- HPV funding, project titles, terms, and abstracts Source
NIH Reporter- Syphilis funding, project titles only Source
NIH Reporter- Syphilis funding, project titles, terms, and abstracts Source
Parkin 2006 Source
Patel et al. 2013 Source
Prabhu Jayalekshmi and Pillai 2012 Source
Rositch et al. 2014 Source
Shrestha and Englund 2010 Source
STD.gov List of All STDs and Their Symptoms Source
Syphilis - CDC Fact Sheet (Detailed) Source
The HPV and Anal Cancer Foundation: Role and Impact Source
The STD Project’s List of All STDs Source
Wald and Corey 2007 Source
Wald and Link 2002 Source
Wang and Ritterband: Herpes Simplex Keratitis Epidemiology Source
Ward and Rönn 2010 Source
WHO GHO DALYs by Cause Source
WHO GHO Data Source
WHO GHO Deaths by Cause Source
WHO: Global Burden of Disease Source
WHO STIs Fact Sheet Source
Wikipedia: Causes of sexually transmitted infections Source
Wikipedia: Herpes simplex Source
Wikipedia: Herpes simplex virus Source
Wikipedia: Human papillomavirus Source
Zuckerman et al. 2009 Source
  • 1.

    “More than 1 million STIs are acquired every day. Each year, there are estimated 357 million new infections with 1 of 4 STIs: chlamydia (131 million), gonorrhoea (78 million), syphilis (5.6 million) and trichomoniasis (143 million). More than 500 million people are living with genital HSV (herpes) infection. At any point in time, more than 290 million women have an HPV infection, one of the most common STIs.” WHO STIs Fact Sheet

  • 2. See Global Burden of Disease 2013: Mortality and Causes of Death Table 2
  • 3.
    • “Over 170 types of HPV have been identified, and they are designated by numbers.[11][12][13]
      Some HPV types, such as HPV-5, may establish infections that persist for the lifetime of the individual without ever manifesting any clinical symptoms. HPV types 1 and 2 can cause common warts in some infected individuals.[citation needed] HPV types 6 and 11 can cause genital warts and respiratory papillomatosis.[2] HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 are considered carcinogenic.[14]Wikipedia: Human papillomavirus
    • “Bivalent, quadrivalent, and 9-valent HPV vaccine all protect against HPV 16 and 18, the HPV types that cause about 66% of cervical cancers and the majority of other HPV-attributable cancers in the United States. 9-valent HPV vaccine targets five additional cancer-causing types, which account for about 15% of cervical cancers (12). Quadrivalent and 9-valent HPV vaccine also protect against HPV 6 and 11, the HPV types that cause anogenital warts.” CDC: HPV Vaccine Information for Clinicians
  • 4. “Safe and highly effective vaccines are available for 2 STIs: hepatitis B and HPV. These vaccines have represented major advances in STI prevention. The vaccine against hepatitis B is included in infant immunization programmes in 93% of countries and has already prevented an estimated 1.3 million deaths from chronic liver disease and cancer.” WHO STIs Fact Sheet
  • 5.

    “Three bacterial STIs (chlamydia, gonorrhoea and syphilis) and one parasitic STI (trichomoniasis) are generally curable with existing, effective single-dose regimens of antibiotics.” WHO STIs Fact Sheet

  • 6.

    “Resistance of STIs—in particular gonorrhoea—to antibiotics has increased rapidly in recent years and has reduced treatment options. The emergence of decreased susceptibility of gonorrhoea to the “last line” treatment option (oral and injectable cephalosporins) together with antimicrobial resistance already shown to penicillins, sulphonamides, tetracyclines, quinolones and macrolides make gonorrhoea a multidrug-resistant organism. Antimicrobial resistance for other STIs, though less common, also exists, making prevention and prompt treatment critical.” WHO STIs Fact Sheet

  • 7.

    See:

  • 8. We averaged the 2013 Global Burden of Disease Study (GBD) and the World Health Organization’s (WHO) Global Health Observatory (GHO) global DALY burden data to get our preliminary estimate of DALY impact size and determine which diseases that are not difficult or impossible to treat or cure met the 5m DALY bar.
  • 9. We speculate that a reason this number is higher than the corresponding number in the GBD 2013 may be because “Other STDs” in the WHO report may include genital herpes, which was calculated separately in GBD 2013.
  • 10.

    The spreadsheet GBD 2013 International Classification of Diseases codes mapped to the Global Burden of Disease cause list cells B94-100 lists the ICD10 codes associated with the STDs for which the overall DALY burden was calculated in the 2013 GBD. We looked up these codes on ICD10 data website to find out what sequelae were included in the impact calculation in the table above. We corresponded with a GBD representative who confirmed that the ICD codes listed in the GBD 2013 International Classification of Diseases codes mapped to the Global Burden of Disease cause list constituted the disease impacts included in the overall disease burden assessment. Note that in one case, we were unable to find the ICD code referenced in the GBD spreadsheet: cells B93, B94, B95 and B97 reference ICD code M73, but we were unable to find that code on the ICD10 website. The list of codes from M70 to M79 does not seem to include M73. We do not know why we were unable to find the code.

    We are uncertain about how the WHO GHO DALY burdens were calculated, and were unable to understand its process based on the information provided on the website (see WHO GHO Data). We reached out to a representative at the WHO GHO and have not received a response. Some information about the WHO GHO methodology and differences compared to the GBD 2010 approach are noted here (WHO: Global Burden of Disease).

    We found that both sources included the impact of neonatal syphilis, the GBD did not include neonatal herpes, chlamydia, or gonorrhea (the DALY burden of each of these broken down by age group can be found at the Global Burden of Disease Study 2013 (GBD 2013) Data Downloads - Full Results by selecting the diseases of interest as the ‘Causes’). The WHO GHO does not have a separate DALY estimate for herpes and very low estimates of the burden of chlamydia and gonorrhea in children under five (both diseases are listed as causing WHO GHO DALYs by Cause) to the extent that we doubt that this accurately captures the effects of the neonatal forms of these diseases.Below, we examine other effects of STDs which are not included in the assessments of the burdens given in the table above.

  • 11.
    • “Before the advent of highly active antiretroviral therapy (HAART), observational data demonstrated an association between non-ulcerative STDs, such as N. gonorrhoeae and C. trachomatis, and the risk of HIV transmission.7 HIV-infected women who had intercurrent N. gonorrhoeae, C. trachomatis, or T. vaginalis had increased rates of HIV detection in the cervix and vagina compared to HIV-infected women who did not have an STD, and HIV-infected men who had N. gonorrhoeae or C. trachomatis were more likely to have higher levels of HIV in the semen than mono-infected controls.8–11 For women, perturbations of the vaginal microflora associated with bacterial vaginosis have also been associated with increased HIV expression in the genital tract.12 In addition, HIV-infected individuals who experienced reactivations of HSV-2 can have high levels of HIV virus recovered from their genital tract ulcers.13Mayer and Venkatesh 2011
    • “Two further cohort studies provide evidence for the possible role of human papillomavirus (HPV) in the sexual transmission of HIV. Auvert and colleagues used data from a male circumcision trial in South Africa to look at the association between HPV and HIV incidence. [24**]After controlling for other factors, there was no association between low-risk HPV and HIV, but there was a 4-fold increased risk in men with high-risk HPV, and the incidence increased with the number of high-risk HPV genotypes detected. A similar finding was reported among MSM in the USA, where increasing numbers of anal HPV types increased HIV risk. [25]” Ward and Rönn 2010
  • 12.

    “With regard to enhanced susceptibility, ulcerative STDs, such as syphilis, Herpes simplex type 2 (HSV-2), and chancroid, result in lesions that cause a breakdown in mucosal integrity and recruit activated target cells containing an enriched population of cells carrying CD4 cell receptors… STDs may also increase the expression of HIV binding ligands which can facilitate HIV acquisition and transmission.” Mayer and Venkatesh 2011

  • 13.
    • “A randomized cross-over trial of herpes simplex virus type 2 (HSV-2)-suppressive therapy (valacyclovir, 500 mg twice daily, or placebo for 8 weeks, a 2-week washout period, then the alternative therapy for 8 weeks) was conducted among 20 Peruvian women coinfected with HSV-2 and human immunodeficiency virus type 1 (HIV-1) who were not on antiretroviral therapy. Plasma samples (obtained weekly) and endocervical swab specimens (obtained thrice weekly) were collected for HIV-1 RNA polymerase chain reaction. Plasma HIV-1 level was significantly lower during the valacyclovir arm, compared with the placebo arm (−0.26 log10copies/mL, a 45% decrease [P<.001]), as was cervical HIV-1 level (−0.35 log10 copies/swab, a 55% decrease [P<001]).” Baeten et al. 2008 (Abstract)
    • “HSV was detected from 29% and 4.4% of swabs on placebo and valacyclovir, respectively (P<0.001). Valacyclovir significantly reduced the proportion of days with detectable seminal HIV-1 (63% during valacyclovir vs. 78% during placebo, p=0.04). The quantity of HIV-1 in semen was 0.25 log10 copies/mL lower (95%CI −0.40 to −0.10, p=0.001) during the valacyclovir arm compared with placebo, a 44% reduction. CD4 count (p=0.32) and seminal cellular CMV quantity (p=0.68) did not predict seminal plasma HIV-1 level.” Zuckerman et al. 2009 (Abstract)
  • 14.
      Mayer and Venkatesh 2011
        • “Over the last decade and a half, there have been several large, multi-center clinical trials conducted in sub-Saharan Africa to evaluate whether the treatment of bacterial STDs could result in decreasing the incidence of HIV transmission and acquisition (see Table I).22 In the Mwanza trial, the only clearly successful STD intervention study, multiple communities in Tanzania were randomized to receive syndromic management of acute bacterial STDs with a regimen that was effective against N. gonorrhoeae, syphilis, and C. trachomatis.23,24 The study was initiated in communities with an average HIV prevalence of 1%, and by the end of the study HIV prevalence was approximately 4% across the sites. By the end of the study, the syndromic management approach resulted in a 29% decrease in syphilis and a 49% reduction in incident urethritis. Although there were no changes in condom use or sexual risk behaviors, there was a statistically significant 38% reduction in HIV incidence. However, several subsequent large interventional STD trials conducted in East Africa were not successful in demonstrating that STD treatment could decrease HIV incidence. In the Rakai study conducted in rural Uganda, the investigators randomized communities to receive periodic mass treatment with a regimen that was effective against N. gonorroheae, C. trachomatis, T. vaginalis, and bacterial vaginosis, as well as syphilis.25 Intervention teams went into villages every 9–10 months to offer the mass treatment. The investigators were able to demonstrate a 20% reduction in syphilis and a 41% reduction in incident T. vaginalis, both of which were statistically significant. However, there was no reduction in HIV incidence in the intervention communities. In contrast to the Mwanza study, the HIV epidemic was already much more well-established in this part of rural Uganda, with an HIV prevalence at the beginning of the study of over 16% in the male population.26,27 Subsequent analyses by researchers in the Rakai group found that the two largest predictors of incident HIV infection among HIV discordant couples were the level of circulating plasma HIV RNA in the infected partner28 and, independently, also the presence of prevalent and incident HSV-2 infection.27 Similar to the Rakai trial, two other large scale clinical trials of STD interventions, one involving syndromic management of STDs as part of a community randomized trial in Masaka, Uganda, and one involving monthly antibiotic chemoprophylaxis conducted among Kenyan female sex workers, did not lead to a decrease in HIV incidence.29,30” See also Table 1 for details on each study.
        • “In 2008, a large randomized controlled trial conducted among HIV uninfected, HSV-2 antibody-positive African women to prevent HIV acquisition, comparing acyclovir to placebo, had no impact.47 Later that year, another large multi-center study among high-risk North and South American MSM and African women who were HIV-uninfected, HSV-2 seropositive failed to show a benefit of acyclovir prophylaxis in decreasing HIV incidence, but unlike the earlier study, this study did show a 47% reduction in genital ulcers.48 More recently, a study of HSV-2 suppressive therapy among HIV-infected and HSV-2 seropositive Africans who were in HIV discordant relationships did not demonstrate a decrease in HIV transmission to their uninfected partners, but did show a decrease in genital ulcers by 73% and plasma HIV viral load by 0.25 log10.49,50 A reason for the failure of acyclovir to prevent HIV acquisition and transmission could be due to the relatively low dosage that was used (400 mg/twice daily), while in some settings a drug concentration several times higher may be used for optimal HSV-2 suppression, particularly in individuals who are already HIV co-infected.51,52 Another reason for the lack of efficacy may be that although acyclovir decreases active clinical shedding of HIV, it may not be sufficiently potent to alter the inflammatory genital tract milieu, including micro-ulcerations, recruitment of cells that can bind or transmit HIV, or other mucosal changes that may potentiate HIV transmission.53
      • “There were three randomized controlled trials that met our inclusion criteria recruited HIV-negative participants with chancroid (two trials with 143 participants) and primary syphilis (one trial with 30 participants). The syphilis study, carried out in the US between 1995 and 1997, randomized participants to receive a single 2.0 g oral dose of azithromycin (11 participants); two 2.0 g oral doses of azithromycin administered six to eight days apart (eight participants); or benzathine penicillin G administered as either 2.4 million units intramuscular injection once or twice seven days apart (11 participants). No participant in the trial seroconverted during 12 months of follow-up. The chancroid trials, conducted in Kenya by 1990, found no significant differences in HIV seroconversion rates during four to 12 weeks of follow-up between 400 and 200 mg single oral doses of fleroxacin (one trial, 45 participants; RR 3.00; 95% CI 0.29 to 30.69), or between 400 mg fleroxacin and 800 mg sulfamethoxazole plus 160 mg trimethoprim (one trial, 98 participants; RR 0.33; 95% CI 0.04 to 3.09). Adverse events reported were mild to moderate in severity, and included Jarisch-Herxheimer reactions and gastrointestinal symptoms. The differences between the treatment arms in the incidence of adverse events were not significant. The quality of this evidence on the effectiveness of genital ulcer disease treatment in reducing sexual acquisition of HIV, according to GRADE methodology, is of very low quality.” Mutua, M’Imunya, and Wiysonge 2012
      • “In the mass treatment trial in rural southwestern Uganda, after three rounds of treatment of all community members for STIs, the adjusted rate ratio (aRR) of incident HIV infection was 0.97 (95% CI 0.81 - 1.2), indicating no effect of the intervention. The three STI management intervention studies were all conducted in rural parts of Africa. One study, in northern Tanzania, showed that the incidence of HIV infection in the intervention groups (strengthened syndromic management of STIs in primary care clinics) was 1.2% compared with 1.9% in the control groups (aRR = 0.58, 95% CI 0.42 - 0.79), corresponding to a 42% reduction (95% CI 21.0% - 58.0%) in HIV incidence in the intervention group. Another study, conducted in rural southwestern Uganda, showed that the aRR of behavioural intervention and STI management compared to control on HIV incidence was 1.00 (95% CI 0.63 - 1.58). In the third STI management trial, in eastern Zimbabwe, there was no effect of the intervention on HIV incidence (aRR = 1.3, 95% CI 0.92 - 1.8). These are consistent with data from the mass treatment trial showing no intervention effect. Overall, pooling the data of the four studies showed no significant effect of any intervention (rate ratio [RR] = 0.97, 95% CI 0.78 - 1.2).

        Combining the mass treatment trial and one of the STI management trials, we find that there is a significant 12.0% reduction in the prevalence of syphilis for those receiving a biomedical STI intervention (RR 0.88, 95% CI 0.80 - 0.96). For gonorrhoea, we find a statistically significant 51.0% reduction in its prevalence in those receiving any of these interventions (RR 0.49, 95% CI 0.31 - 0.77). Finally, for chlamydia, we found no significant difference between any biomedical intervention and control (RR 1.03, 95% CI 0.77 - 1.4).” Ng et al. 2011

    Note that there is overlap between the studies examined in the reviews above.

  • 15. For example, for HSV, the potential impact seems very large. This is because:
    • In an observational study from 2002, researchers found that approximately 20% of cases of HIV at their study site appeared to be attributable to HSV-2 when 22% of the population was infected with HSV-2.[1] We have a very limited understanding of the reliability or methodology of these studies.
    • In several studies from the 1990s and 2000s, the percentage of the population infected with HSV-2 in various countries was within a factor of 2-4 of that the HSV-2 prevalence in the observational study.[2] We do not know if genital HSV-1 has been linked to HIV transmission. We note that it seems possible that other factors (e.g. likelihood of engaging in sexual intercourse while experiencing an outbreak of genital herpes) could potentially drive differences in HSV-driven HIV transmission even in regions where HSV-2 infection prevalence rates are similar.
    • The global burden of HIV is estimated to be approximately 80M DALYs.[3] 80M*0.2=16M DALYs that could potentially be attributable to HSV-driven HIV transmission. We don’t know whether HIV cases that are attributable to HSV are representative of HIV cases in general in terms of their DALY burden.

    However, we note that if STDs increase HIV transmission, HSV may be responsible for a larger share of these transmission events than other STDs because it is highly prevalent.[4]

    [1]“For 9 cohort and nested case-control studies that documented HSV-2 infection before HIV acquisition, the risk estimate was 2.1 (95% confidence interval, 1.4–3.2). Thus, the attributable risk percentage of HIV to HSV-2 was 52%, and the population attributable risk percentage was 19% in populations with 22% HSV-2 prevalence but increased to 47% in populations with 80% HSV-2 prevalence. For 22 case-control and cross-sectional studies, the risk estimate was 3.9 (95% confidence interval, 3.1–5.1), but the temporal sequence of the 2 infections cannot be documented.” Wald and Link 2002

    [2] *”HSV-2 infections are markedly less frequent than HSV-1 infections, with 15%–80% of people in various populations infected (Corey and Wald, 1999). The rates of infection vary with country as well as levels of sexual activity. In some countries, such as Spain and the Philippines, the HSV-2 prevalence hovers around 10%, increasing to 20%–30% range for most European countries and the United States (Varela et al., 2001; Smith et al., 2001; Enders et al., 1998; Malkin et al., 2002). Developing countries bear a much higher burden of HSV-2 infection, with many populations in Africa having >50% prevalence in the general population (Weiss et al., 2001).” Wald and Corey 2007 (although we did not vet those prevalence estimates, and note that that many are over a decade old).

    *”The estimated total number of people aged 15–49 years who were living with HSV-2 worldwide in 2003 is 536 million (Table 1). More women than men were infected, with an estimated 315 million infected women compared to 221 million infected men. The number infected increased with age, most markedly in the younger ages, until it peaked in the age stratum 35–39 years of age, after which it declined slightly.” Looker Garnett and Schmid 2008

    [3] It was estimated to be 91,907,414 DALYs by the WHO in 2012 (see WHO GHO DALYs by Cause), and 69,363,400 DALYs by the GBD in 2013 (see GBD 2013 DALYs from all causes cell C7). We used 80M as a rough average of the two estimates.

    [4] For example: “A cohort study of women in two African countries, Zimbabwe and Uganda, followed 4439 women every 3 months for up to two years. [20**]With the exception of syphilis, which was uncommon, all the reproductive tract infections were associated with HIV in at least one statistical model. After controlling for demographic and behavioural factors, the strongest risk was from gonorrhoea, which conferred a 7-fold increase in HIV incidence, but the highest population attributable risk percent (PAR%) was for sero-prevalent HSV-2 (50.4%), with incident HSV-2 contributing 7.9%, gonorrhoea 5.3%, and bacterial vaginosis 17.2%.” Ward and Rönn 2010

  • 16.
    • “Two further cohort studies provide evidence for the possible role of human papillomavirus (HPV) in the sexual transmission of HIV. Auvert and colleagues used data from a male circumcision trial in South Africa to look at the association between HPV and HIV incidence. [24**]After controlling for other factors, there was no association between low-risk HPV and HIV, but there was a 4-fold increased risk in men with high-risk HPV, and the incidence increased with the number of high-risk HPV genotypes detected. A similar finding was reported among MSM in the USA, where increasing numbers of anal HPV types increased HIV risk. [25]” Ward and Rönn 2010
    • “Three studies provided sufficient data to allow calculation of the proportion of HIV infections attributable to prevalent HPV infection (Table 3). 21 and 37% of HIV infections in women in studies in Zimbabwe[24] and South Africa[29] were attributable to infection with prevalent HPV of any genotype at the visit prior to HIV acquisition. 28% of HIV infections in Kenyan heterosexual men[30] were attributable to infection with HPV at baseline.” Houlihan et al. 2012
  • 17. “It is biologically plausible that prevalent HPV may increase the risk of HIV acquisition. It has been demonstrated that the E7 protein of HPV type-16 down-regulates an epithelial adhesion molecule called E-Cadherin[39], potentially increasing permeability of the genital lining to HIV. The lining of the genital tract contains Langerhans’ cells (LC), which can internalise HIV, preventing onward infection[40]. In HPV-infected tissue, a reduced density and altered morphology of LCs has been demonstrated[41-43]. The host immune response to HPV is mediated by T-lymphocytes[44], and this response may increase HIV risk since T-lymphocytes are primary target cells for HIV. An increased presence of these cells has been seen in HPV-infected cervical tissue[45]. Further, HPV non-persistence, which is likely to be associated with a T-lymphocyte influx, was associated with HIV acquisition in 2 studies in this review[24, 26], when persistent infection was not. Elevated levels of cytokine IL-Iβ, which activates a promoter region in the HIV genome[46], have also been demonstrated in women with HPV-associated abnormal cervical cytology[47] and defensins and thrombospondins, anti-HIV proteins, are also lower in precancerous cervical lesions[48] (although in this review cytological abnormalities were not associated with HIV acquisition[23, 26]).”Houlihan et al. 2012
  • 18. “There are currently two vaccines that provide near 100% protection against persistent infection with HPV-16 and 18, two highly prevalent genotypes that are responsible for 70% of invasive cervical cancer cases and a relatively smaller fraction of other HPV-associated cancers. This raises the question as to whether individuals who receive HPV vaccination will have the added benefit of lowering risk of HIV infection [5,21]. Since there are currently no data to directly estimate this, we used our observational data to examine risk of HIV acquisition among men infected with vaccine-preventable types 16/18, taking into account other concurrent HPV infections” Rositch et al. 2014
  • 19. “Genital herpes is a sexually transmitted disease (STD) caused by the herpes simplex viruses type 1 (HSV-1) or type 2 (HSV-2).” Genital Herpes - CDC Fact Sheet (Detailed)
  • 20.
    • “We fitted a constant-incidence model to pooled HSV-1 prevalence data from literature searches for 6 World Health Organization regions and used 2012 population data to derive global numbers of 0-49-year-olds with prevalent and incident HSV-1 infection. To estimate genital HSV-1, we applied values for the proportion of incident infections that are genital.
      Findings
      We estimated that 3709 million people (range: 3440–3878 million) aged 0–49 years had prevalent HSV-1 infection in 2012 (67%), with highest prevalence in Africa, South-East Asia and Western Pacific. Assuming 50% of incident infections among 15-49-year-olds are genital, an estimated 140 million (range: 67–212 million) people had prevalent genital HSV-1 infection, most of which occurred in the Americas, Europe and Western Pacific.” Looker et al. 2015

    Looker Garnett and Schmid 2008

    • “The large majority of persons with genital herpes do not know they have the disease and infection and reactivation are typically “asymptomatic” although, with teaching, most persons with positive HSV-2 serology (46 of 53, in one study) recognize genital lesions.”
    • “The estimated total number of people aged 15–49 years who were living with HSV-2 worldwide in 2003 is 536 million (Table 1). More women than men were infected, with an estimated 315 million infected women compared to 221 million infected men. The number infected increased with age, most markedly in the younger ages, until it peaked in the age stratum 35–39 years of age, after which it declined slightly.”
  • 21. “Nationwide, 15.5 % of persons aged 14 to 49 years have HSV-2 infection. 21 The overall prevalence of genital herpes is likely higher than 15.5% because an increasing number of genital herpes infections are caused by HSV-1.” Genital Herpes - CDC Fact Sheet (Detailed)
  • 22. “There is no cure for herpes. Antiviral medications can, however, prevent or shorten outbreaks during the period of time the person takes the medication. In addition, daily suppressive therapy (i.e. daily use of antiviral medication) for herpes can reduce the likelihood of transmission to partners.

    Several clinical trials have tested vaccines against genital herpes infection, but there is currently no commercially available vaccine that is protective against genital herpes infection. One vaccine trial showed efficacy among women whose partners were HSV-2 infected, but only among women who were not infected with HSV-1. No efficacy was observed among men whose partners were HSV-2 infected. A subsequent trial testing the same vaccine showed some protection from genital HSV-1 infection, but no protection from HSV-2 infection. 17” Genital Herpes - CDC Fact Sheet (Detailed)

  • 23. “The updated Global Burden of Disease Study (GBD) estimates that genital HSV resulted in 311,600 years lived with disability (YLD) in 2013 (95% uncertainty interval 98,300–748,500) due to genital ulcer disease alone [18]. GBD 2013 likely underestimates the impact of genital HSV, as these YLD estimates do not include disability due to neonatal herpes nor the contribution of genital HSV to HIV susceptibility, which are the most devastating consequences of infection.” Johnston, Gottlieb, and Wald 2016

    See also GBD 2013 DALYs from all causes, cell C80

    The impacts of genital herpes included in this assessment can be found in the GBD 2013 International Classification of Diseases codes mapped to the Global Burden of Disease cause list cell B99. See the ICD codes associated with the GBD genital herpes assessment here (ICD 10 Data: Anogenital herpes).

  • 24.
    • “The frequency of neonatal herpes varies by region and is estimated to occur from 1 in 3200 to 1 in 15000 pregnancies (Sullivan-Bolyai et al., 1983a; Tookey and Peckham, 1996; Mindel et al., 2000; Brown et al., 2003; Gutierrez et al.,1999)” Wald and Corey 2007. We do not know what regions are represented in this estimate, and whether the frequency has changed since it was made.

    • “The HSV-2 epidemic is of concern in part because of its potential to cause neonatal herpes.11,24,49,97 Through pooling of prevalence values by age and sex in a random-effect model, followed by the use of a constant-incidence model, the worldwide prevalence of HSV-2 among 15- to 49-year-olds is estimated to be 536 million (16%).48 NHANES data from 1999–2002 showed that 63% of pregnant women in the United States were seropositive for HSV-1, 22% for HSV-2, and 13% for both.96 The incidence of neonatal HSV was estimated to be 5.9 per 100,000 live births in a nationwide surveillance program in Canada and ranged from 5.8 to 11.5 per 100,000 live births in the United States.14 Various manifestations of ocular infection occur in an estimated 13–20% of neonates with HSV.54,61Farooq and Shukla 2012

    We did not vet these estimates or investigate the methodologies used in these studies.

  • 25.
    • “Untreated neonatal HSV infection is associated with only a 40% survival rate, and even with the early initiation of high-dose intravenous acyclovir therapy, it results in considerable disability among survivors.” Corey and Wald 2009, p. 1376.
    • “The mortality rate [of neonatal HSV infection] is relatively high (24%), and long-term sequelae may occur.” Clinuvel: Herpes Simplex Virus. We are uncertain about how this document arrived at the 24% figure, and could not find an explanation or source.

    • Another study found a mortality rate of 0.8/100,000 live births in California from 1995-2003: “The overall incidence of neonatal herpes was 12.1 per 100,000 live births per year, with no observable change from 1995 to 2003. Neonatal herpes-related mortality, which was estimated to be 0.8 deaths per 100,000 live births, also did not show significant change over time.” Morris et al. 2008 (Abstract), indicating an overall mortality rate 6.6% (0.8 death rate from neonatal HSV/12.1 incidence of neonatal HSV) of neonatal HSV cases.

    We would guess that the mortality rate might be higher in the developing world, where HSV may be more common and access to antivirals and diagnostic tools may be more limited, but we don’t know if this is true, and if so, how much higher it might be.

  • 26. There are approximately 135M births/year (CIA World Factbook, 525600 minutes/year*256 births/minute=134,553,600 births/year).
  • 27. For example if 10,000 people would have lived to 70 years of age but die in infancy due to neonatal HSV each year, the DALY impact would be 700K. Note that this estimate is excluding the burden on infants that don’t die but live with disability as a result of HSV, which we understand to be substantial. Also note that these years are not discounted because the 2013 Global Burden of Disease does not use a discount rate, and we felt that it was useful to make the numbers more comparable.
  • 28. We use the following estimate of severe vision loss from HSV: “One way to estimate vision loss in HSV would be to determine the proportion of HSV keratitis cases that lead to blindness in the affected eye and extrapolate this to annual incidence rates. A Moor-fields Eye Hospital study found that of 152 patients with epithelial keratitis, only 3% had a final visual acuity less than 20/200.93 Final visual acuity ranged from 20/60 to 20/200 in 24%, and 20/20 to 20/40 in 73%. Liesegang et al found a slightly lower incidence of vision impairment in ocular HSV (3 of 131 cases); impairment was defined as an acuity worse than 20/100, however, and the series included diseases other than keratitis.47 Final visual acuity was 20/40 or better in 78% of eyes. A study at the Aravind Eye Hospital in India found that at least 2% had visual acuity worse than 20/1200, and 62% improved to better than 20/40.31 Norn et al found nearly 6% of eyes were worse than 20/200, although some were treated with idoxuridine or steroids.64 In one series 20% of HSV uveitis cases led to severe vision loss; this did not include cases of uveitis without keratitis, which would be considered additive.55 Although blindness can occur via ocular HSV without corneal involvement (e.g., acute retinal necrosis), these cases are much rarer.

    There were several factors that needed to be considered in projecting the rates of vision loss from HSV keratitis (Table 6). Based on these issues, and adjusting the Moorfields data for the effect of long-term antiviral treatment (which reduces the rate of recurrence), we estimate that at least 1.5% of clinically significant HSV keratitis leads to vision worse than 20/200, the WHO definition of severe visual impairment in developed nations (Table 6). This is based on the assumption that a reduction in recurrence rate leads to a proportional decrease in visual impairment. It is slightly lower than the rate of visual impairment in the Rochester study, where acyclovir was available for only a portion of the study period. In the developing world, including Africa and India, it may be 3% or higher as access to treatment is often severely limited, and other risk factors may play a role. We are unable to estimate the proportion of cases leading to monocular blindness (lower than 20/400). Longer study periods might reveal higher rates of vision loss as there would be more time for recurrences.

    Using the available data on visual prognosis, therefore, our conservative estimate is that HSV keratitis is the cause of roughly 40,000 new cases of severe monocular visual impairment or blindness annually in the world (Table 7).” Farooq and Shukla 2012. Table 7 includes data about HSV keratitis incidence. We have not vetted this estimate.

  • 29. For example, we read that, “[m]ost HSV eye disease occurs in adults, developing many years after the primary infection (mean age of presentation, late fifth to early sixth decade of life). Herpetic keratitis in children commonly involves the corneal epithelium and stroma and is marked by a disproportionate risk of bilateral disease, high recurrence rate, and amblyopia.” Wang and Ritterband: Herpes Simplex Keratitis Epidemiology
  • 30. “In the presence of a certain gene variation (APOE-epsilon4 allele carriers), a possible link between HSV-1 (i.e., the virus that causes cold sores or oral herpes) and Alzheimer’s disease was reported in 1979.[39] HSV-1 appears to be particularly damaging to the nervous system and increases one’s risk of developing Alzheimer’s disease. The virus interacts with the components and receptors of lipoproteins, which may lead to the development of Alzheimer’s disease.[40] This research identifies HSVs as the pathogen most clearly linked to the establishment of Alzheimer’s.[41] According to a study done in 1997, without the presence of the gene allele, HSV-1 does not appear to cause any neurological damage or increase the risk of Alzheimer’s.[42] However, a more recent prospective study published in 2008 with a cohort of 591 people showed a statistically significant difference between patients with antibodies indicating recent reactivation of HSV and those without these antibodies in the incidence of Alzheimer’s disease, without direct correlation to the APOE-epsilon4 allele.[43] It should be noted that the trial had a small sample of patients who did not have the antibody at baseline, so the results should be viewed as highly uncertain. In 2011 Manchester University scientists showed that treating HSV1-infected cells with antiviral agents decreased the accumulation of β-amyloid and P-tau, and also decreased HSV-1 replication.[44]Wikipedia: Herpes simplex virus
  • 31.
    • “A herpetic infection of the brain thought to be caused by the transmission of virus from a peripheral site on the face following HSV-1 reactivation, along the trigeminal nerve axon, to the brain. HSV is the most common cause of viral encephalitis. When infecting the brain, the virus shows a preference for the temporal lobe.[14] HSV-2 is the most common cause of Mollaret’s meningitis, a type of recurrent viral meningitis.” Wikipedia: Herpes simplex
    • “Benign recurrent aseptic meningitis is a rare disorder described by Mollaret in 1944. When initially described, this form of aseptic meningitis had no identifiable infecting agent. New sophisticated diagnostic tools have now identified herpes simplex type 2 virus as the most commonly isolated agent. Antiviral treatment has been used successfully for prophylaxis and treatment.” Farazmand Woolley and Kinghorn 2011 (Abstract)

    We were unable to find quantitative information about the prevalence and impact of Mollaret’s meningitis, but our impression from our reading is that it is rare.

  • 32. “Herpes whitlow is a painful infection that typically affects the fingers or thumbs. On occasion, infection occurs on the toes or on the nail cuticle. Individuals who participate in contact sports such as wrestling, rugby, and football(soccer), sometimes acquire a condition caused by HSV-1 known as herpes gladiatorum, scrumpox, wrestler’s herpes, or mat herpes, which presents as skin ulceration on the face, ears, and neck. Symptoms include fever, headache, sore throat, and swollen glands. It occasionally affects the eyes or eyelids.” Wikipedia: Herpes simplex
  • 33. Human papillomavirus vaccines: WHO position paper, October 2014
    • “Based on a meta-analysis, the adjusted HPV prevalence worldwide among women with normal cytological findings was estimated to be 11.7% (95% confidence interval (CI): 11.6–11.7%).2 The highest adjusted prevalence was found in sub-Saharan African regions (24%; 95% CI: 23.1–25.0%), Latin America and the Caribbean (16.1%; 95% CI: 15.8–16.4%), Eastern Europe (14.2%; 95% CI: 14.1–14.4%), and south-eastern Asia (14%; 95% CI: 13.0–15.0). However, country-specific adjusted HPV prevalence in cervical specimens ranged from 1.6% to 41.9% worldwide. Age-specific HPV prevalence peaked at younger ages (<25 years) with a prevalence of 21.8% (95% CI: 21.3–22.3%, crude) and 24.0% (95% CI: 23.5– 24.5%, adjusted), with a lower prevalence plateau at middle-ages.”
    • “HPV prevalence in men: A systematic review of genital HPV among men in sub-Saharan Africa found that the prevalence of any HPV type ranges between 19.1% and 100%.5 The estimated pooled prevalence of any HPV was 78.2% (95% CI: 54.2–91.6%) among HIV-positive men and 49.4% (95% CI: 30.4–68.6%) among HIV-negative men (p=0.0632). No clear age trend was observed. The most common high-risk HPV types were HPV-16 and HPV-52, and HPV-6 was the most common low-risk HPV type in the general population.

      A systematic review of genital HPV-DNA prevalence in men examined data generally limited to men >18 years of age from Europe and North America.6 The estimated HPV prevalence in men peaked at slightly older ages than in women and remained constant or decreased slightly with increasing age. HPV prevalence was high in all regions but varied from 1% to 84% among low-risk men, and from 2% to 93% among high-risk men (e.g. sexually transmitted infection (STI) clinic attendees, HIV-positive males, and male partners of women with HPV infection or abnormal cytology). HIV-positive men who have sex with men showed the highest prevalence. Anal HPV infections are very common in men who have sex with men, and almost universal among those who are HIV-infected.7

      A multicentre clinical trial (conducted in 18 countries from Africa, Asia-Pacific, Europe, Latin America and North America) examined the baseline prevalence of penile, scrotal, and perineal/perianal HPV infection in heterosexual men. The prevalence of any HPV type was 18.7% at the penis, 13.1% at the scrotum, 7.9% at the perineal/perianal region, and 21.0% at any site. HPV was most prevalent in African men and least prevalent in men from the Asia-Pacific region. Age was not associated with risk of positivity for HPV types 6, 11, 16, 18, or any tested HPV types. Having at least 3 lifetime female sexual partners had the greatest impact on HPV prevalence: odds ratio (OR) 3.2 (95% CI: 2.1–4.9) for HPV types 6, 11, 16, and 18; and OR 4.5 (95% CI: 3.3–6.1) for all HPV types tested.8

  • 34. “Human papillomavirus (HPV) is a very common virus that infects epithelial tissue. More than 120 HPV types have been identified. Most HPV types infect cutaneous epithelial cells and cause common warts, such as those that occur on the hands and feet. Approximately 40 HPV types infect mucosal epithelial cells on the genitals, and the mouth and throat. Although most HPV infections are asymptomatic and resolve spontaneously or become undetectable, some HPV infections can persist and lead to cancer.
    Persistent infections with high-risk (oncogenic) HPV types can cause cancers of the anus, cervix, penis, vulva, and vagina, as well as the oropharynx (defined as the back of the throat, including the base of the tongue and tonsils). The most common high-risk types are 16 and 18.

    Infection with low-risk (non-oncogenic) HPV types can cause genital warts and rarely laryngeal papillomas. These types can also cause benign or low-grade cervical cell abnormalities. The most common low-risk HPV types are 6 and 11.” CDC: HPV Vaccine Information for Clinicians

  • 35. “It is important to note that HPV vaccines are highly efficacious as a 3-dose schedule in women aged 18–26 years for prevention of CIN 3; data on efficacy for prevention of cervical cancer are pending.49” Human papillomavirus vaccines: WHO position paper, October 2014

    We understand CIN 3 to refer to severely abnormal cervical intraepithelial neoplasia, a precursor to cervical cancer, based on this definition of CIN 3.

  • 36.
    • “Bivalent, quadrivalent, and 9-valent HPV vaccine all protect against HPV 16 and 18, the HPV types that cause about 66% of cervical cancers and the majority of other HPV-attributable cancers in the United States. 9-valent HPV vaccine targets five additional cancer-causing types, which account for about 15% of cervical cancers (12). Quadrivalent and 9-valent HPV vaccine also protect against HPV 6 and 11, the HPV types that cause anogenital warts.” CDC: HPV Vaccine Information for Clinicians
    • “Gardasil 9 is a vaccine approved for use in females ages 9 through 26 and males ages 9 through 15. It is approved for the prevention of cervical, vulvar, vaginal and anal cancers caused by HPV types 16, 18, 31, 33, 45, 52 and 58, and for the prevention of genital warts caused by HPV types 6 or 11. Gardasil 9 adds protection against five additional HPV types—31, 33, 45, 52 and 58— which cause approximately 20 percent of cervical cancers and are not covered by previously FDA-approved HPV vaccines.” FDA News Release: Gardasil 9
  • 37.
    • “Virtually all cases of cervical cancer are caused by HPV, and just two HPV types, 16 and 18, are responsible for about 70 percent of all cases (7,8).” National Cancer Institute: HPV Vaccine Fact Sheet
    • “HPV-16 and HPV-18 were the most common HPV types in invasive cervical cancer during the period 1940–2007 with no statistically significant variations in their adjusted-relative contributions from 1940–1959 to 2000–2007 (HPV-16 from 61.5 to 62.1%, and HPV18 from 6.9 to 7.2%).12 HPV types 16, 18, 45, 31, 33, 52, and 58 account for approximately 90% of the squamous-cell carcinomas which are positive for HPV DNA.11Human papillomavirus vaccines: WHO position paper, October 2014
  • 38. Human papillomavirus vaccines: WHO position paper, October 2014

    • “Cervical HPV infection can be diagnosed using tests based on HPV-DNA performed on cervical or vaginal swabs; HPV-induced changes in the cervical epithelium can be detected by cytology using a microscopic examination of exfoliated cells, known as the Papanicolaou (Pap) test. Testing for HPV DNA, cytology, and visual inspection with acetic acid are used for cervical cancer screening. In low-resource settings, visual inspection of the cervix with acetic acid is used to identify cervical lesions.29, 30 Anogenital warts are diagnosed by visual inspection including anoscopy.”

    • “Although there is no virus-specific treatment for HPV infection, the HPV-related diseases can be treated by tissue destructive measures. In low-income countries, precancerous lesions of the cervix are most commonly treated by cryotherapy.31 Surgical excision of the affected tissue is also effective (loop electrosurgical excision procedure) and necessary when the lesion is large.29, 31 Excision by cone biopsy is reserved for more advanced or recurrent cases, especially those involving disease in the endocervical canal. Screening and treatment for preinvasive disease of the cervix is highly successful in preventing progression to cervical cancer.29
  • 39. “The majority (70%–90%) of HPV infections with both high and low risk types are asymptomatic and resolve spontaneously within 1–2 years. In some instances, persistent infection with the high-risk types may ultimately progress to invasive carcinoma at the site of infection, mainly of the genital tract, if not detected and treated appropriately. Persistent HPV infection is a necessary cause of cervical cancer.10Human papillomavirus vaccines: WHO position paper, October 2014
  • 40. “The interval between the acquisition of HPV infection and progression to invasive carcinoma is usually about 10 years or longer.” Human papillomavirus vaccines: WHO position paper, October 2014
  • 41. “Cervical cancer is the fourth most common cancer in women, and the seventh overall, with an estimated 528,000 new cases in 2012. As with liver cancer, a large majority (around 85%) of the global burden occurs in the less developed regions, where it accounts for almost 12% of all female cancers. High-risk regions, with estimated ASRs over 30 per 100,000, include Eastern Africa (42.7), Melanesia (33.3), Southern (31.5) and Middle (30.6) Africa. Rates are lowest in Australia/New Zealand (5.5) and Western Asia (4.4). Cervical cancer remains the most common cancer in women in Eastern and Middle Africa.

    There were an estimated 266,000 deaths from cervical cancer worldwide in 2012, accounting for 7.5% of all female cancer deaths. Almost nine out of ten (87%) cervical cancer deaths occur in the less developed regions. Mortality varies 18-fold between the different regions of the world, with rates ranging from less than 2 per 100,000 in Western Asia, Western Europe and Australia/New Zealand to more than 20 per 100,000 in Melanesia (20.6), Middle (22.2) and Eastern (27.6) Africa.” Globocan Cervical Cancer Fact Sheet

  • 42. “Persistent HPV infection is a necessary cause of cervical cancer.10Human papillomavirus vaccines: WHO position paper, October 2014
  • 43. GBD 2013 DALYs from all causes cell C101

    The number of fatalities from cervical cancer and estimated DALY burden appear to be in agreement. 6,900,000 DALYs/528,000 cases of cervical cancer=13 DALYs/case of cervical cancer.

  • 44. WHO GHO DALYs by Cause, “Cervix uteri cancer”
  • 45. “Most anal squamous cell cancers (80%) are caused by HPV, usually HPV-16.18” Human papillomavirus vaccines: WHO position paper, October 2014

    “IARC26 considers that there is convincing evidence that infection with HPV 16,18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 or 66 can lead to cervical cancer. For HPV 16, the evidence further supports a causal role in cancer of the vulva, vagina, penis, anus, oral cavity and oropharynx and a limited association with cancer of the larynx and periungual skin. HPV 18 also shows a limited association with cancer at most of these sites. Evidence for associations of HPV types of genus beta with squamous cell carcinoma of the skin is limited for the general population. There is some evidence that HPVs are involved in squamous cell carcinoma of the conjunctiva, but inadequate evidence for a role of HPVs in cancer of the esophagus, lung, colon, ovary, breast, prostate, urinary bladder and nasal and sinonasal cavities.

    With respect to cancer of the cervix, oncogenic HPV may be detected by PCR in virtually all cases of cervix cancer, and it is generally accepted that the virus is necessary for development of cancer, and that all cases of this cancer can be ‘attributed’ to infection.10

    With respect to squamous cell cancers of the vulva and vagina, carcinoma of the penis and anal cancer, published studies do not allow quantification of relative risk and infection prevalence, because they are generally small in size and usually do not include comparable measurement of prevalence of infection at these sites in normal subjects. To estimate AFs, approximate estimates of the proportion of cancer cases infected with HPV in various series are used.

    The prevalence of HPV in vaginal cancer is about 60–65% in studies using PCR methodology.26, 27 About 20–50% of vulvar cancers contain oncogenic HPV DNA,28, 29 but only the basaloid and warty type that tends to be associated with vulvar intraepithelial neoplasia is caused by HPV infection (prevalence 75–100%), and only 2–23% of the keratinizing carcinomas harbour HPV.30 HPV-related vulvar cancer occurs in younger women than the typical keratinizing squamous histology related to chronic inflammatory precursors. Vulvar carcinomas are generally rather more frequent than cancers of the vagina; an overall HPV prevalence of about 40% in cancers of the lower genital tract in women is assumed. For anal cancer, in a large series of cases from Denmark and Sweden 95% and 83% of cancers involving the anal canal in women and men, respectively, were positive for oncogenic HPV31; the AF is taken to be 90% worldwide. For penile cancer, HPV DNA was found in 30% of 71 cases of penile cancer from Brazil32 and in 42% of 148 cases from the USA and Paraguay;33 the AF is assumed to be 40%.

    HPV probably plays a role in the aetiology of a fraction of cancers of the oral cavity and pharynx,34 although the major risk factors are, of course, tobacco and alcohol. Several studies have investigated prevalence of HPV in cancers of the mouth and pharynx.35, 36 On average ˜40% of tumours were HPV-positive, but the prevalence varied widely with the population studied, subsites, type of specimen and detection method. HPV was detected most commonly in oropharynx and tonsil, but at every subsite, HPV 16 was the predominant type.37 The largest study so far is a multicentre case-control study in 9 countries, including more than 1,600 cases of cancers of the mouth and oropharynx and 1,700 controls.38 HPV DNA was detected in tumour specimens (cases) by PCR, and presence of antibodies against HPV 16 L1 and HPV 16 E6 and E7 was tested for by ELISA methods in cases and controls. HPV DNA was detected in 4 and 18% of cancers of the mouth and oropharynx, respectively (HPV 16 was found in 95% of the positive cases). As HPV DNA cannot be evaluated in controls, and there was a good correlation between HPV DNA in cancer biopsies and serum anti-E6/E7 antibodies, a comparison was made between HPV-positive cases who were positive for HPV DNA or E6/E7 antibody (6.4% mouth cancers, 15.3% oropharyngeal cancers), and HPV-positive control subjects positive for anti E6 or anti-E7 antibody (1.6%). The AFs, based on these figures, would be 5% for mouth cancers and 16% for cancers of the oropharynx. However, assessment of HPV DNA presence by PCR assay may lead to an overestimation of cases in which the virus is etiologically involved, as suggested by the lower proportion of cases with E6/E7 expression39––4.6% of oral cancers and 12% of oro-pharyngeal cancers in the IARC multinational study.38 The corresponding OR’s and AFs would be 2.9 and 3% for mouth cancers and 9.2 and 12% for oropharynx cancers. For the purpose of estimation, it is assumed that 3% of oral cavity cancers and 12% of cancers of the oropharynx are attributable to HPV.” Parkin 2006

  • 46. See Table III of Parkin 2006. We divided the number of cases of cervical cancer by the total number of HPV-attributable cancers in Table III (492900/561200) and find that 87.8% of HPV-attributable cancers were cervical cancers in 2006. This implies that 12.2% of HPV-attributable cancers are not cervical cancers, but rather are cancers of the vulva, vagina, penis, anus, mouth, or oropharynx (as listed in the table).

    We note that the relative proportions of HPV-attributable cancers may have changed since the publication of Parkin 2006, but we did not investigate this.

  • 47. “HPV-6 and HPV-11 can also cause a rare condition known as recurrent respiratory papillomatosis (RRP), in which warts form on the larynx or other parts of the respiratory tract. RRP occurs mainly in children younger than 5 years (juvenile-onset RRP)23 or in persons in the third decade of life (adult-onset RRP).24 In rare cases, women with genital HPV infection may transmit the virus to an infant during childbirth.25 Untreated RRP can become seriously debilitating due to airway obstruction.” Human papillomavirus vaccines: WHO position paper, October 2014
  • 48. “It is still not apparent whether HPV is a causal factor of lung cancer or whether it is just an opportunistic pathogen in the lung cancer tissue and the exact molecular mechanisms behind it. Almost all of the signalling pathways having a role in lung cancer are found to be altered or blocked by human papilloma viral proteins initiating tumorigenesis. Further evidence is mandatory to substantiate beyond doubt the causative role of HPV in the lung tissue tumorigenesis. Moreover, the cofactors supplementing the HPV in the transformation processes are yet to be classified.” Prabhu Jayalekshmi and Pillai 2012
  • 49. Wikipedia: Human papillomavirus
    • “Skin infections with HPV can cause noncancerous skin growths called warts (verrucae). Warts are caused by a rapid growth of cells on the outer layer of the skin.

      In one study, infection by HPV types 2, 27, and 57 were found in people with warts, while infection by HPV types 1, 2, 63, and 27 were found in people with clinically normal skin”
    • “In very rare cases, HPV may cause epidermodysplasia verruciformis in immunocompromised individuals. The virus, unchecked by the immune system, causes the overproduction of keratin by skin cells, resulting in lesions resembling warts or cutaneous horns.[65]
  • 50. “After controlling for past sexual behaviors, vaccinated women had a lower risk of testing positive for the 4 types included in the HPV vaccine (6, 11, 16, or 18; Table 1). This association became stronger when the number of recent sexual partners was controlled for. However, vaccinated women had a higher prevalence of nonvaccine high-risk types than unvaccinated women (61.5% vs 39.7%, prevalence ratio 1.55, 95% CI 1.22-1.98). After adjusting for the number of recent sexual partners, the difference in prevalence of high-risk nonvaccine types was reduced, but remained significant.” Guo et al. 2015

    But see:
    “The bivalent vaccine induces strong neutralizing antibody responses (>50% seropositivity) to HPV-31, HPV- 33, HPV-45, and HPV-52. The quadrivalent vaccine induces neutralizing antibody responses to HPV-31, HPV- 33 and HPV-52. Serum-neutralizing antibody responses against non-vaccine HPV types have been reported to be broader and of a higher magnitude in the bivalent versus quadrivalent vaccine recipients. The clinical significance and longevity of this cross-protection are unclear.77, 78, 79 The vaccines appear to differ in their degree of cross protection.80Human papillomavirus vaccines: WHO position paper, October 2014

  • 51. “Syphilis is a sexually transmitted disease (STD) caused by the bacterium Treponema pallidum.” Syphilis - CDC Fact Sheet (Detailed)
  • 52. “The primary symptoms may include small sores, cuts or bumps on genitals or mouth. Body rash on palms, feet and other parts of the body may follow. When untreated for extensive period of time, syphilis can start destroying body functions and lead to mental, neurological problems, heart diseases, blindness and even death. Infected pregnant women can easily pass syphilis to their children.” STD.gov List of All STDs and Their Symptoms
  • 53. Syphilis - CDC Fact Sheet (Detailed)
    • “There are no home remedies or over-the-counter drugs that will cure syphilis, but syphilis is easy to cure in its early stages. A single intramuscular injection of long acting Benzathine penicillin G (2.4 million units administered intramuscularly) will cure a person who has primary, secondary or early latent syphilis. Three doses of long acting Benzathine penicillin G (2.4 million units administered intramuscularly) at weekly intervals is recommended for individuals with late latent syphilis or latent syphilis of unknown duration. Treatment will kill the syphilis bacterium and prevent further damage, but it will not repair damage already done.”
    • “Although data to support the use of alternatives to penicillin is limited, options for non-pregnant patients who are allergic to penicillin may include doxycycline, tetracycline, and for neurosyphilis, potentially ceftriaxone. These therapies should be used only in conjunction with close clinical and laboratory follow-up to ensure appropriate serological response and cure.”
  • 54. GBD 2013 deaths from syphilis cells M397 and M19
  • 55. See the WHO GHO Deaths by Cause
  • 56. Cell M397 of IHME-Data-Syphilis-DALYs from Global Burden of Disease Study 2013 (GBD 2013) Data Downloads - Full Results and WHO GHO DALYs by Cause
  • 57.

    GBD 2013 International Classification of Diseases codes mapped to the Global Burden of Disease cause list lists syphilis in row 95, as a subcategory of “Sexually transmitted diseases other than HIV”, and the corresponding ICD disease codes listed in cell B95 do not appear to include HIV among the sequelae of syphilis.

  • 58. Some examples of current organizations we are aware of in this space include:

    The HPV and Anal Cancer Foundation appears to be active (see The HPV and Anal Cancer Foundation: Role and Impact) and had in ~$760K in assets 2013 (see 990 Finder: HPV and Anal Cancer Foundation Form 990 2013). We don’t know how much of that was for HPV R&D.

  • 59. NIH Estimates of Funding for Various Research, Condition, and Disease Categories (RCDC) This does not appear to include HIV/AIDS. There is a separate line for “HPV and/or cervical cancer vaccines”
  • 60. based on looking at NIH Estimates of Funding for Various Research, Condition, and Disease Categories (RCDC) and the titles of all NIH grants larger than $500k from 2015 from the NIH 2015 STD/Herpes project listing
  • 61. See Foundation giving based on Foundation Center data sheet “FDO categories” cell E256 for “public health, STDs” our blog post What Large-Scale Philanthropy Focuses on Today
  • 62. Grantome.com “sexually transmitted”
  • 63. Specifically, we read that:
  • 64. Grantome.com “herpes simplex”
  • 65. The first figure includes only grants in which “herpes simplex” was included in the project title, while the latter also includes grants in which “herpes simplex” was included in the project abstract or project terms.
    To access this data, we went to the NIH Project Reporter, and:
    • In “Fiscal Year”, unselected “active projects” and selected “2015”
    • In “Text Search” entered “herpes simplex”
    • In “Limit Project search to” selected “Project Title”
    • Clicked “Submit Query”
    • Clicked “Data and Visualize”
    • Repeated this process, instead selecting “Project Title” “Project Terms” and “Project Abstracts” rather than just “Project Title”

    See NIH Reporter- Herpes simplex funding, project titles only cell C7 and NIH Reporter- Herpes simplex funding, project titles, terms, and abstracts cell C20

  • 66. Grantome.com “hpv”
  • 67. NIH Estimates of Funding for Various Research, Condition, and Disease Categories (RCDC) line for “HPV and/or cervical cancer vaccines”
  • 68. The first figure includes only grants in which “hpv” was included in the project title, while the latter also includes grants in which “hpv” was included in the project abstract or project terms.
    To access this data, we went to the NIH Project Reporter, and:
    • In “Fiscal Year”, unselected “active projects” and selected “2015”
    • In “Text Search” entered “hpv”
    • In “Limit Project search to” selected “Project Title”
    • Clicked “Submit Query”
    • Clicked “Data and Visualize”
    • Repeated this process, instead selecting “Project Title” “Project Terms” and “Project Abstracts” rather than just “Project Title”

    See NIH Reporter- HPV funding, project titles only cell C10 and NIH Reporter- HPV funding, project titles, terms, and abstracts cell C27

  • 69. Grantome.com “syphilis”
  • 70. The first figure includes only grants in which “syphilis” was included in the project title, while the latter also includes grants in which “syphilis” was included in the project abstract or project terms.
    To access this data, we went to the NIH Project Reporter, and:
    • In “Fiscal Year”, unselected “active projects” and selected “2015”
    • In “Text Search” entered “syphilis”
    • In “Limit Project search to” selected “Project Title”
    • Clicked “Submit Query”
    • Clicked “Data and Visualize”
    • Repeated this process, instead selecting “Project Title” “Project Terms” and “Project Abstracts” rather than just “Project Title”

    See NIH Reporter- Syphilis funding, project titles only cell C6 and NIH Reporter- Syphilis funding, project titles, terms, and abstracts cell C15

  • 71. From the NIH 2015 STD/Herpes project listing
  • 72. We searched with keywords: “STD” “STI” “Sexually-transmitted” “Venereal” “HPV” “Herpes” and “Syphilis”
  • 73. We searched for “std nonprofits” “sexually transmitted disease R&D” “center for std research” “std research” and “syphilis nonprofit”