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.
1. 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.
1.1 Size of the problem
1.1.1 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)|
|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.
1.1.2 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 [email protected], 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.
1.1.3 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.
1.1.4 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 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).
2. 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.
2.1 How much funding is in this area?
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.
- 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
3. 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:
- Looked at NIH funding by disease and the titles of all NIH grants larger than $500k from 2015 from the Sexually Transmitted Diseases/Herpes category.71
- Looked at the dataset from our blogpost “What Large-Scale Philanthropy Focuses on Today”.
- Searched the Foundation Center’s 990 finder for organizations working on STD research and development in general, or on our diseases of interest.72
- Conducted Google searches73
- Read through grants.gov funding opportunities for STDs.
- Looked at the NIH budget request.
- Searched Guidestar.org for organizations relevant to STD research (keywords: “sexually transmitted diseases”).
4. 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?
|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|
|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|
|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 “herpes simplex”||Source|
|Grantome.com “sexually transmitted”||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|
|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|