New STDs and HIV

Table of Contents

Background
Importance of STDs
Human Papilloma Virus (HPV)
HTLV-1
Mycoplasma genitalium
Mobilluncus sp.
Helicobacter cinaedi and Helicobacter fennelliae
Human Herpes Virus 8 (HHV-8)
Syphilis
Gonorrhea
Chlamydia
Herpes Virus (HSV)
HIV/AIDS
Student Questions

Readings

Background

The eight big STDs are listed here. They fall into four categories. The first category is comprised of two bacterial infections, gonorrhea and chlamydial infection, which infect the mucous membranes and cause very similar conditions - urethritis in the male, cervicitis in the female, and the complications that go along with these. The second group is composed of another two very similar bacteria, or diseases, Haemophilus ducreyi that causes chancroid and Treponema pallidum that causes syphilis. They both cause genital ulcers because they infect the skin as well as the mucous membranes. They have some other similarities, such as increasing the efficiency of HIV transmission, probably to a greater extent than do most STDs. Syphilis is also associated with congenital syphilis.

There are also two categories of viral STDs that are frequently listed as the most important. They include HIV and hepatitis B, which are similar in the sense that they are not only spread by sex but also by blood. They also both have major complications: AIDS for HIV and liver cancer and cirrhosis for hepatitis B. The other group is composed of herpes simplex virus (HSV) and human papillomavirus (HPV). These two are somewhat similar to the other group in the sense that they infect skin and mucous membranes, sometimes causing lesions, sometimes not; and they also have major complications. HSV can cause perinatal herpes, HPV can cause cervical cancer.

Importance of STDs

These estimates come from the World Health Organization (WHO). Using data from prevalence studies from the mid-1990s and knowledge about the natural histories of these infections, the WHO calculated an estimate of yearly STD incidence. The most common ones are gonorrhea and trichomonas infection.

The Centers for Disease Control and Prevention (CDC) published the above table in 1995. Among the top ten reportable infectious diseases, chlamydial infection, gonorrhea, and AIDS, which are all STDs, are at the top. Shigella and hepatitis A are both transmitted by oral-anal contact in gay men. Primary and secondary syphilis ranks number 8 on the list, but has been declining in incidence in the U.S. Hepatitis B is transmitted predominantly by sex and intravenous drug use.

STD Direct and Indirect Costs in 1994
STDs other than AIDS Sexually transmitted HIV Total	$10 Billion $7 Billion $17 Billion

The Institute of Medicine (IOM) tried to get an estimate of the costs, direct and indirect, due to STDs. They estimated that the direct costs plus the indirect costs for STDs, other than AIDS, was about US$10 billion. For HIV it was about US$7 billion, for a total of $US17 billion. However, there was a mistake made in preparing these estimates. Indirect costs often are about three times direct costs for adult diseases. In this report indirect costs were underestimated; the analyst divided by 3 instead of multiplying by 3!

Another reason STDs have been viewed as important is their association with HIV transmission. The STDs are not only associated with their own morbidity, but they facilitate sexual transmission of HIV.

Examples of Major Epidemiological Studies Regarding the Risk of Subsequent HIV Infection Among Persons with Existing STDs
Reference (Study Site: Population)	STD: RR or OR (95% CI)
Cameron et al., 1989 (Nairobi: Male STD patients) Plummer et al., 1991 (Nairobi: Female sex workers) Laga et al., 1993 (Kinshasa: Female sex workers) Telzak et al., 1993 (New York: Male STD patients) Kingsley et al., 1990 (U.S.: Men who have sex with men) Nyange et al., 1994 (Mombasa: Female sex workers)	GUD: 4.7 (1.3, 17) GUD: 3.3 (1.2, 10.1), Ct: 2.7 (0.9, 7.8) Gc: 4.8 (2.4, 9.8), CT: 3.6 (1.3, 11.0), Tr: 1.9 (0.9, 4.1) GUD: 3.3 (1.1, 10.1) Hs: 1.0 (0.3, 2.9) GUD: 4.0 (1.6, 9.9), Sy: 6.5 (1.5, 27.9) Gc: 1.8 (1.0, 9.9)
CT = chlamydial infection; GUD = genital ulcerative disease; Gc = gonorrhea; Hs = herpes simplex virus type 2 infection; Sy = syphilis; Tr = trichomoniasis

There are a large number of cohort studies, some listed above, that have shown that when people are studied prospectively, acquisition of the sexually transmitted disease is temporarily associated with a subsequently increased risk of acquiring HIV. For genital ulcer diseases, often due to chancroid and syphilis in these African studies [SLIDE 1], and more often related to herpes in subsequent studies, the risk of HIV acquisition is increased. Trichomoniasis was associated with increased risk in a couple of studies. A number of subsequent studies have looked at gonorrhea and chlamydia, and most recently bacterial vaginosis has been linked to HIV in three prospective studies in Africa. All of these studies examine the affect of STD on increasing susceptibility to HIV, but not the affect on increasing the infectivity of HIV seropositive individuals. Other studies have shown that certain urethral, cervical, vaginal and anorectal infections, as well as genital and anorectal ulcers, increase the amount of HIV shedding in genital and anorectal secretions in the ulcer exudate - indirect evidence for a probable effect on infectiousness.

Newly Recognized and Newly Emergent Sexually Transmitted Pathogens, 1976-1998
STD Pathogens	Associated Syndromes
HPVs (1976 - present) HTLV-I (1980) HTLV-II (1982) Mycoplasma genitalium (1981) Mobiluncus sp. (1980, 1983) Helicobacter cinaedi    and H. fennelliae (1983) HIV-1 (1983) HIV-2 (1986) HHV type 8 (1995)	Genital & anal warts, dysplasias, and cancers T-Cell leukemia/lymphoma; tropical spastic paraparesis ? Nongonococcal urethritis BV-associated Proctocolitis Cellulitis, fever, bacteremia in the immunosuppressed AIDS AIDS Kaposi's Sarcoma, body cavity lymphoma

These are the organisms that I classify as newly recognized or newly emergent over the last quarter century. Many of them are obviously quite important.

Human Papilloma Virus (HPV)

The first of the HPVs was cloned in 1976. Since then, there have been about a hundred found, of which about one third are genital types. [SLIDE 2] This is an electron micrograph of HPV. [SLIDE 3] These are the warts that HPV causes. They really represent the tip of the iceberg of HPV. As I mentioned, there are over a hundred different types of HPV, each different from the other in terms of DNA sequence. [SLIDE 4] The ones of particular interest are the ones highlighted here in yellow, which are the ones that are most strongly associated with cervical cancer. Type 16 is responsible for about half of all cervical cancers, and then types 18 and 45 pick up another large percentage. It has been possible to show that over 97-98% of cervical cancers are associated with HPV.

Laura Koutsky and colleagues here at the University of Washington have followed women prospectively before they had any HPV and have identified the point of acquisition after they have had a new sexual partner. [SLIDE 5] For those who never acquired HPV, as determined by repeated screening of the cervix for HPV DNA, only 0.03% developed cervical dysplasia. Of those who were HPV DNA positive, 48%, almost half, ultimately developed cervical dysplasia. Being HPV positive included any HPV of any type. Cervical dysplasia included any degree of squamous intraepithelial lesions, but was nearly always mild in severity.

[SLIDE 6] In contrast, these are cohort studies that we did in the STD clinic in Seattle a few years earlier. Women were followed prospectively and the point in time they first acquired HPV in their cervix was ascertained. Here we are looking at the cumulative proportion that developed biopsy-confirmed cervical intraepithelial neoplasia grade 2 or 3 (or moderate to severe dysplasia). You can see that for those who had HPV-16 or 18 only, about 40% developed severe dysplasia and for those who had 16 or 18 plus other types it was about 50%. The question of why these women went on to develop severe dysplasia when the college students only developed mild dysplasia is an intriguing one. We found significant associations with the presence of certain other STDs, and we think that other STDs at the time may have been risk factors. There was some hint that multiple HPV infections might also be a risk factor. In any case, there was a very close correlation between HPV and dysplasia.

An interesting thing that came out of these studies is that not all HPVs are alike.

Risk for Biopsy-Confirmed CIN 2-3 Associated with HPV16 Variants
Variant	No. of CIN 2-3/ No. of Subjects (%)	RR*	95% CI
HPV16 PL	4/45 (8.9 %)	1.0
HPV16 NPL	5/12 (41.7 %)	6.5	1.6-2.7.2
* Adjusted for lifetime number of sexual partners, HPV16 status at entry, ethnic group, and number of visits positive for HPV16.

This study compares HPV-16 called prototype-like, representing the standard HPVs that have been around in everybody's laboratory for a long time, versus non-prototype-like HPV 16 which are variants that differ in terms of their DNA sequence from the standard prototype. The non-prototype-like HPV 16 were associated with about a six- to seven-fold increased risk of CIN 2-3, compared with prototype-like HPV 16 infection. This represents HPV variants that presumably emerged at some point in the past, which are even more strongly associated with moderate to severe dysplasia than HPV 16 in general. It is not know what virulence factors in these variant HPVs cause higher risk of dysplasia.

[SLIDE 7] This looks at the age-specific incidence rates of cervical cancer. In situ cancers peak at an early age, around the same time that the HPV infections peak in women. The incidence of cervical cancer occurs much later in life, after the incidence of carcinoma in-situ decreases and disappears. So there is this very long incubation period, and the pathogenesis of what is going on during this time is not entirely clear.

HPV cannot be grown in tissue culture yet, but it is possible to clone the major surface proteins called L-1 and L-2 into other bacteria. The vaccinia will grow in tissue culture and coat themselves with the surface proteins of HPV. That can be used to produce huge amounts of the protein. [SLIDE 8] Here you see these pentamers of L-1 expressed on vaccinia virus. Virus-like particles from vaccinia or other systems are now being used to produce tests for HPV immune responses, as well as HPV vaccines. I think this is probably going to be the second STD after hepatitis B where a vaccine has actually been developed, and there is reason to be optimistic about this working. Similar vaccines developed against animal papilloma viruses have been effective in preventing infection.

Vaccines may be used prophylactically in order to prevent infection. They do elicit neutralizing antibodies and inhibit attachment or entry into the epithelial cell. They can also in theory be used post-infection. For example, in treating refractory genital warts, vaccines could be used to stimulate production of HPV-specific cytotoxic T lymphocytes that kill the cells that are infected with the virus, and to inhibit viral replication. Vaccines could also in theory be used as therapeutic vaccines for women with cervical cancer. The genes thought to be most strongly associated with inducing cancer, that are expressed in the oncogenic HPV types, are E-6 and E-7. The proteins made by these genes have also been put into candidate vaccines and are being evaluated as treatment for cervical cancer.

HTLV-1

Human T-cell lymphotropic virus, HTLV-1, was first discovered in 1980 and is now clearly recognized as sexually transmitted, particularly in the Caribbean and parts of Latin America. It is associated with a leukemia/lymphoma syndrome and also with a disease of the spinal cord called TSP, or tropical spastic paraparesis. A neurologist here at the University of Washington, Dr. Joseph Zunt, has shown that in Peru some of the same factors that affect shedding of HIV from the cervix in women, namely chlamydial infection and cervical ectopy, are also associated with increased risk of shedding of HTLV-1.

Mycoplasma genitalium

Mycoplasma genitalium was discovered in 1981. [SLIDE 10] This is M. genitalium, one of three genital mycoplasms. The other two are Mycoplasma hominus and Ureaplasma urealyticum.

There was a question as to whether this organism was associated with non-Gonococcal urethritis (NGU). There are only about 30 isolates in the history of the world so far as of 1999-2000, but the organism can be detected by PCR testing. Mycoplasma genitalium looks to be relatively important in genital infections where it may behave like gonorrhea and chlamydia. [SLIDE 11] This is an old University of Washington study examining the rate of persistent or recurrent NGU after diagnosis and treatment with the standard approach of tetracycline or doxycycline. For the patients who had chlamydia, a common cause of NGU, only 19% recurred. For the patients who did not have chlamydia, the recurrence rate was 39%. For those who had Ureaplasma urealyticum, the recurrence rate was about 32%, and for those who had neither chlamydia nor Ureaplasma urealyticum, the rates of recurrence were the highest, 52%.

In the clinical world of STDs, the problem of recurrent NGU is a big one. Does M. genitalium play a role? I will not present that data because they are not published yet. Margot Schwartz, Pat Totten, and others were able to demonstrate that M. genitalium was significantly associated with NGU, and is about as common in NGU as chlamydia is now. Chlamydial infection was associated with about 25% of NGU cases, and M. genitalium with about 20% of cases in the Seattle study. We are examining whether this bacteria causes disease in women as well. One syndrome in women called mucopurulent cervicitis, involves inflammation of the cervix. Chlamydia can be a cause, but most cases are idiopathic, and M. genitalium could be the culprit.

M. genitalium is an example of a bug that is probably been around for a long time, but is difficult to grow. It turns out that it is the smallest living bacteria and it has the smallest genome of any bacterial species. It was one of the first bacteria to be completely cloned. Now it is possible to go and pick out parts of the genome to amplify by PCR, and that is how our studies have been proceeding with M. genitalium.

Mobilluncus sp.

[SLIDE 12] This is the typical appearance of the discharge from the vagina in bacterial vaginosis (BV). It is very common in STD clinics. Nobody had a clue as to what this really represented. In the 1970's we began to get involved in the studies.

[SLIDE 13] The normal vaginal flora are shown here. A normal vaginal epithelial cell does not have a lot of bacteria attached to it. The bacterium with the blue color is a gram-positive rod, which is known as lactobacillus. We used to call them Lactobacillus acidophilus, but it turns out those in the vagina usually are not that particular species. They are Lactobacillus crispatis and Lactobacillus jensenii. They make lactic acid and produce hydrogen peroxide, and that peroxide mixes in the normal vagina with chloride ion and with an enzyme, myeloperoxidase or lactoperoxidase, which results in bleach and makes the vagina fairly resistant to other bacteria. But in some women, these H2O2-producing lactobacilli disappear and are replaced by large numbers of other organisms, which include Gardnerella vaginalis.

[SLIDE 14] The replacement organisms also include these curved rods. These turned out to be anaerobic bacteria. They are called Mobilluncus sp. because they have this flagellum, which makes them mobile, and the word uncus, is Latin for "curved." There are two species of them, and they are very highly associated with BV. You can find them in about 50% of women with BV and 0% of women without BV.

In the United States, the prevalence of BV is approximately 5% for Caucasians, 10-15% for Hispanics, and 15-30% for African Americans. In Africa, a number of studies have shown that the prevalence is as high as 50%. That is why the attributable risk of BV for HIV might be very high, even though the relative risk is 2 or 3.

The potential for hygiene being important in transmission of BV-associated organisms from men to women is being explored. Based on this study we are trying a hygiene intervention, where the man is the target of the intervention. The outcome is to prevent recurring BV in women whom we have treated.

Helicobacter cinaedi and Helicobacter fennelliae

Helicobacter cinaedi and Helicobacter fennelliae were also discovered in the early 1980's and were associated with "gay-bowel disease." As risk-taking changed in men having sex with men (MSM) during the AIDS era, the proctocolitis syndrome disappeared. But as these men developed AIDS, these same organisms reappeared in the blood of immunosuppressed patients in association with cellulitis, fever, and bacteremia. Up to 1990, there had been 22 isolates of one of these organisms from people with those symptoms and as of a couple of years ago, there were about sixty that had been sent to the CDC. So here is a great example of an emerging infection. It first emerged with the epidemic of STDs among MSM, primarily in association with frequent oral-anal contact. It disappeared with decreased risk-taking in MSM, then reappeared with different clinical manifestations when MSM became immunosuppressed.

Human Herpes Virus 8 (HHV-8)

The most recent on my list is HHV-8, which was discovered in 1995. HHV-8 is associated with a variety of syndromes, including Kaposi's sarcoma (KS). Here is a virus that was always around in association with Kaposi's sarcoma, which was, until AIDS, a fairly uncommon syndrome that mostly involved elderly men in the Mediterranean. It has emerged as a much more common infection now in the era of AIDS immunosuppression. [SLIDE 16] This is a patient with Kaposi's sarcoma of the palette. HHV-8 is very strongly associated with this lesion. There are a number of epidemiological studies around the country trying to figure out how this organism is transmitted. It is not entirely clear. It seems to be common in saliva and uncommon in semen. However, HHV 8 seropositivity is clearly associated with number of sexual partners.

Syphilis

There is good news in the world of emerging STDs. Part of that is the decrease of syphilis in the United States. [SLIDE 17] This shows the rates of early syphilis in the U.S., and you can see that we are at lower rates of syphilis now than we ever have been in this country. For 1999 the drop is continuing. Almost 80% of the U.S. counties had no syphilis last year.

Bad news includes the fact that primary and secondary syphilis, HIV seroprevalence, and gonorrhea rates are all highest in the Southeast. [SLIDE 18] That is where the curable STD problem is in the United States. Heterosexual HIV is emerging as a predominant pattern of transmission in these areas. Further, the percentage of isolates of N. gonorrhoeae from men who have sex with men (MSM) has risen in eight cities participating in the CDC's gonorrhea isolates surveillance project. [SLIDE 19]

We think the increase is due to recurrent high risk-taking in the era of highly active anti-retroviral therapy (HAART). You could argue that maybe this increase in percentage of gonococcal isolates that are from MSM is because we are doing a good job controlling heterosexual gonorrhea. However, it turns out that there is an absolute increase as well as a relative increase in cases of gonorrhea involving MSM. Furthermore, looking at international trends, even though the U.S. rate of gonorrhea and syphilis are decreasing we still are 10 to 100 times higher in gonorrhea and syphilis rates than other industrialized countries. [SLIDE 20] Other countries really have eliminated these diseases.

The syphilis data from Public Health - Seattle-King County shows that after apparently eliminating endemic syphilis in 1996, it reappeared. The first few cases of early syphilis involved heterosexuals and imported cases, but the infection soon became endemic in MSM population. [SLIDE 21] Through 1999, there has been a steady increase of the number of cases of primary and secondary syphilis and 85% are in gay men. About 2/3 of these MSM are HIV seropositive and their average number of sex partners in the previous four months is 4 or 5. The partners were almost all met in anonymous venues like bathhouses. In Washington State about 80% of all syphilis in the pre-AIDS era was in MSM. This is a re-emerging infection, the old patterns of transmission are recurring and we need to do something about it. We need to re-address risk-taking in this population.

Gonorrhea

[SLIDE 22]These are the data for gonorrhea in the U.S. up until 1998. The rates are going back up for the first time in many years in all regions of the country. The increases disproportionally involve MSM in some areas. For example, in Seattle, more than half of the cases that we see in the STD clinic are in MSM.

The good news is that gonorrhea has been going down in the United States up until last year. The bad news concerns antimicrobial resistance of the gonococcus globally.

This study from 1994 looked at ciprofloxacin resistance in the Philippines. [SLIDE 23] The importance of ciprofloxacin is that it is the only oral drug that works for gonorrhea that is available over the counter, at a cheap price and is on the essential drug list for all developing countries. So it has become the mainstay for treating gonorrhea in order to prevent HIV transmission throughout the developing world. Before 1994, 0.03 micrograms per ml or less of ciprofloxacin inhibited essentially all gonococci. In 1994, 92 consecutive isolates from female sex workers in Manila and Cebu contained many strains with intermediate levels of susceptibility to ciprofloxacin. As a result of these findings, we decided to do a treatment trial where we compared ciprofloxacin treatment to cefixime, a drug that we use widely here in the United States for gonorrhea.

We went back to the same areas in 1996 and did a randomized trial. [SLIDE 24] The results showed that during these 18 months more resistant strains emerged that represented half of all of the isolates. This showed how quickly antibiotic resistance can emerge.

Various microbial mutations are associated with resistance to quinolones. In 1994, most of the strains had only one mutation in the Gyrase A (GyrA) gene. A few had two mutations. By the time we went back in 1996, most of the resistant strains had multiple mutations, some involving GyrA, some involving ParC. In this short period of time, strains apparently had acquired this step-wise increase in number of mutations leading to high-level resistance that has since become widespread throughout Asia. It is interesting that the first beta lactamase producing gonococcus was detected in the Philippines in 1972, and now high level ciprofloxacin resistance has first become widespread in the Philippines. One of the risk factors for this level of resistance was related to use of over the counter antibiotics.

Chlamydia

[SLIDE 25] This is typical of the yellow discharge from the endocervix, in this case caused by chlamydia, before treatment and after treatment with doxycycline. Unlike syphilis and gonorrhea, it was not a reportable disease in the U.S. until fairly recently. [SLIDE 26] The reported rate per 100,000 population has been steadily going up, mainly because the proportion of states requiring reporting of chlamydial infection steadily increased. Within all of the states, the number of people being tested is also increasing due to newer diagnostic tests that are easier to use - for example, testing urine by DNA amplification methods. A better way to look at trends in chlamydia rates in the U.S. therefore is serial prevalence testing. The first region of the country to actually begin screening for chlamydia was Region X.

The prevalence of chlamydial infection initially dropped in Region X, and some other Regions, after introduction of screening of women attending family planning clinics. However, the prevalence has leveled off, and we have not yet figured out how to get it any lower than 3%. The thought is that by being more effective in screening men, doing outreach through adolescent clinics, and doing a better job of partner notification we could get rates even lower. But we are not at the point of eradication.

Herpes Simplex Virus (HSV)

[SLIDE 29] Here is a picture of recurrent herpes. [SLIDE 30] These are the data from the National Health and Nutrition Examination Survey (NHANES) done around 1991. The survey included serologic testing for serum antibody to HSV. [SLIDE 31] The first thing that was apparent was the difference between racial and ethnic groups. The prevalence of HSV antibody is around 80% for African-Americans and 20% for Caucasians. How much of the age-related increment is due to a cohort effect and how much to actual continuing risk taking as the population ages is not clear. What was interesting was to look at the trends in HSV 2 seroprevalence comparing the NHANES study in 1978 to the NHANES study in 1991. In males, there was an overall increase from 13.4% to 17.1%; and in females, a 32% increase during the AIDS era. Perhaps condoms do not work as well for preventing herpes transmission as they do for preventing HIV, or behavioral interventions developed to prevent HIV transmission in groups at high risk for HIV have had less impact on the behaviors of the general population at risk for HSV.

HIV/AIDS

HIV-1 was discovered in 1983 and HIV-2 in 1986. Now a variety of types and subtypes have been recognized. We can no longer track trends in HIV transmission by following adult cases of AIDS, because many people who acquire HIV are eventually put on highly active antiretroviral therapy (HAART) which greatly reduces progression to AIDS. On the other hand, if we monitor trends in reported cases of AIDS in adolescents and young adults, we are looking at something closer to AIDS incidence.

U. S. Trends in AIDS Incidence in Adolescents and Young Adults (Ages 13 - 25 Years)
	No. Reported AIDS Cases
	1990	1995	% Change
MSM IDU Heterosexual contact	1400   600   380	1300   550   900	- 7%   - 8% + 73%
Paul Denning, Patricia Fleming. Abstract 375 4th Conference Retroviruses and Opportunistic Infections, 1997

Between 1990 and 1995 there had been a drop in the number of cases of AIDS among MSM 13 to 25 years old. There had also been a drop in the number of cases in intravenous drug users (IDU). However, there was a 137% increase in AIDS cases attributed to heterosexual transmission such that the numbers in young heterosexuals (900 in 1995) here were beginning to approach the numbers in MSM (1300 in 1995).

U. S. Trends in AIDS Incidence in Adolescents and Young Adults (Ages 13 - 25 Years)
	No. Reported AIDS Cases
	1990	1995	% Change
White Hispanic Black	950 500 850	800   600 1400	- 16%    + 20% + 150%
Paul Denning, Patricia Fleming. Abstract 375 4th Conference Retroviruses and Opportunistic Infections, 1997

By ethnic group, we see a drop in reported AIDS among young Caucasians, a modest increase in young Hispanics, and a very big increase in young African-Americans. Clearly, this is an epidemic that is moving into the African-American population in the United States. Among adolescents, more than half of all of the new cases among MSM was in African-Americans. Even in the traditional risk groups, it is moving into the African-American population.

Adults and children estimated to be living with HIV/AIDS as of 1999
People with HIV or AIDS
Sub-Saharan Africa  S. and SE Asia  Latin America  North America  Western Europe  E. Asia and Pacific  Caribbean  N. Africa, Middle East  E. Europe, Central Asia  Australia, New Zealand	24.5 million 5.6 million 1.3 million 900,000 530,000 520,000 420,000 360,000 220,000 15,000
Total	35.2 million

Globally, as of the end of 1999, there were about 33.6 million people living with HIV/AIDS. The cumulative number of deaths was 16 million. So if you add these up, there are about 50 million total cases of HIV globally. That is about 6 million new cases per year and about 10,000 new cases per day. There were 2.6 million deaths due to HIV/AIDS in 1999

What about intervention? A lot of people say it is too late, we cannot do anything about HIV/AIDS now. The World Bank looked at this. They published a book called Confronting AIDS, and they published a subsequent book with the background papers. I would highly recommend people read this book.  

Distribution of Developing Country  Population by Stage of Epidemic
Stage of Epidemic	Total Population	Percent
Nascent Concentrated Generalized Unknown	2,422 1,624   220   467	51%    34%      5%    10%
Total	4,733	100%
Number of countries	135	VanVliet et al. 1997

Fifty-one percent of the world's population still lives in an area where even the high-risk groups have not been infected yet. Thirty-four percent have concentrated epidemics where only MSM or sex workers have rates exceeding 5% and only 5% of the world's population is in areas that have a generalized epidemic where more than 5% of the general population is infected.

The epidemic is really going wild in South Africa. In 1990, there were hardly any cases. Then apartheid was lifted, which allowed people to move into the country easily and to move from rural to urban areas. The movement of people upset the standards of behavior, which has resulted in the current situation. Subtype C has exploded in this area.

HIV evolves 100 million times faster than the human genome. There are 10 million viral copies per person per day, this is a virus that is changing even as we watch it emerge. It would be naïve to think that these changes are not going to influence the epidemiology, the pathogenesis, the treatment, and the prevention of this infection. Subtype B, which we have in the United States and Latin America, are only about 10% of all HIV. The diversification is proceeding so fast that the difference between subtypes is disappearing.

Global HIV rates are increasing and subtypes are diversifying. In Western Europe, HIV rates are decreasing, bacterial STDs are decreasing or eliminated and viral STDs such as herpes and HPV are continuing. In Eastern Europe, however, STDs and HIV rates are increasing. This is not due only to increased reporting. If you look at prevalence in occupational groups that have been screened, there is a 100-fold increase in HIV prevalence. In North America, HIV/AIDS rates are decreasing in MSM, but risk behaviors are relapsing, and rates will likely increase. The incidence of HIV/AIDS is rising in the heterosexual population especially in adolescents, women, African-Americans, and Hispanics.  

What socioeconomic and behavioral factors underlie the global epidemic of HIV, and epidemics of STD in some populations? Among many important factors are the following:

1. Most importantly, poverty and income inequalities.
2. Global population growth. [SLIDE 33]
3. The changing age structure of the population where increasing absolute and relative numbers of adolescents destabilize cultural traditions and allow many types of risk-taking to increase.
4. Migration from rural to urban areas, and other population movements related to war, famine, and work, with sex ratio inequalities that help drive prostitution. [SLIDE 34]
5. In the U.S. and the Caribbean, the crack cocaine epidemic. [SLIDE 35]
6. In the U.S., the increasing concentration of poverty in the inner cities is a factor. If you take the middle class out of the cities, you reach a "tipping point" where sociocultural stability suddenly deteriorates. It is like taking the control rods out of a nuclear reactor and allowing it to go critical.

Student Questions

Q: Is the assumption that increased transmission of HIV in the presence of STDs is due to the STD itself? My assumption would be that it is due to more partners.

A: All of these studies were prospective and attempted to answer this question. They not only were able to make the temporal association of first the STD, then the HIV seroconversion, but they were able to get good documentation prospectively of how many partners the individuals had and the types of practices.

What that does not control for is the type of partner. Maybe these people were the same in terms of numbers of partners but were choosing higher risk partners. That is a flaw of all cohort studies in general, but there are a lot of good biological data that also support this link. One of them came from a study from Mike Cohen that was published in Lancet a couple of years ago that looked at how much free virus was shed in semen. He found that in the presence of gonorrhea infection prior to treatment, there were between 150 and 200 thousand copies of HIV per milliliter of semen. After treatment, within a week or two, this number had dropped to below that level.

A study done on the borders of Lake Victoria, where twelve communities were randomly assigned to get an early STD diagnosis and treatment intervention, or served as controls. They divided them up into six pairs of communities. Six got the intervention and six did not. In every community that got the intervention, there was a significant reduction in the risk of HIV transmission. Overall, there was about a 40% reduction in HIV incidence in the communities that got the improved syndromic management of STDs. That is the only study of its kind that has demonstrated anything that prevents sexual transmission of HIV.

Subsequently, some of you have probably heard of the Rikai study in Uganda that looked at whether or not mass treatment of a whole population would affect incidence of HIV. They found that when they randomized 50 plus communities to get mass treatment with azithromycin, ciprofloxacin, and metronidazole, or no such treatment, that there was no impact on HIV. Unfortunately, there was hardly any impact on STDs either. The study was probably flawed by the problem of diffusion of infection contamination by people going from the villages that got the intervention to those that did not. There was a significant reduction of trichomoniasis and latent syphilis, but no significant impact on gonorrhea, chlamydia, early syphilis, or bacterial vaginosis. 

Q: An issue that has come up repeatedly is to what extent are we seeing new technology enhancing diagnostics and therefore our understanding of the infectious agents, and to what extent are ecological factors really bringing forward infections?

A: Both are factors. HPV was recognized using new technology. You cannot grow it but DNA cloning and PCR methods allowed recognition and epidemiolgic studies. However, in the U.S., The actual incidence of HPV (at least of the type that causes genital warts) - also increased 5-10 fold from the mid-60s to the mid to late 80s, so people started amplifying it.

Q: Is there any difference in the clinical presentation of BV with or without Mobilluncus sp.? Is there any thought about what role Mobilluncus sp. may play in BV?

A: The pathophysiology of BV beyond the absence of peroxide-producing lactobacilli is not well understood. The organisms that are statistically significantly associated with it are Gardnerella vaginalis, Mobiluncus sp., Mycoplasma hominus, and Ureaplasma urealyticum, and several anaerobic bacteria. Without going into this in detail, there is tremendous interest in BV now because of the increased susceptibility of women with BV to HIV. The specific role of Mobiluncus sp. is not yet understood - but note that it seems that 50% of women with BV do not have Mobiluncus.

Q: In order to understand the role of condom use in herpes prevention, have studies looked at the location of the herpes lesions on the penis? Whether they are really distal or proximal?

A: Nobody has looked at that yet, as far as I know. That is a plausible explanation as to why condoms might not work so well for preventing herpes transmission in some cases - they may not always prevent contact of infected skin with uninfected skin. With diseases like gonorrhea or chlamydia, urethral contact at the cervix should be prevented by condom use. However, the prospective study of couples who were serodiscordant for HSV 2 infection and who have participated in HSV 2 vaccine trials may give better data on the actual effectiveness of condoms.

Q: What is the difference between Western Europe's prevention and control methods versus ours in terms of how they were able to accomplish what we have not?

A: That is a good question. Ann Downer, who is in the Health Services Department, at the UW School of Public Health, did a Ph.D. thesis on this. For example, Sweden has offered K-12 education on sex and family health since the 1940s. As a result, the current generation of politicians and religious leaders has gone through it, so they are sympathetic to this type of education. There is not a lot of opposition to it. Secondly, they have very active non-governmental organizations, which provide condoms so that they are readily available to people all around Sweden. Thirdly, they have developed youth clinics that deal comprehensively with STDs, contraception, suicide, depression, and other problems of youth. In Sweden, which has a population of about 8 to 10 million, there are about 200 of these youth clinics, many of which are school-associated. I think Western Europe in general is regarded as having taken this on seriously.

You contrast that with the United States. Everything that is done officially in this country seems to be designed to oppose STD/HIV prevention. Congress canceled a survey of adult sexual behavior, the adolescent health study and antenatal screening in women. The media generally have not allowed condom ads to be on television. Congress prohibits needle exchange programs. There are inadequate methadone slots for heroin addicts. The largest federal grants for school-based prevention programs require abstinence-only teaching.

Q: Could you comment on some earlier studies looking at resistance rates with gonorrhea and use of penicillin and then quinolones?

A: I think that is a very interesting question. What happens when these resistance mutations first emerge, whether it is in the gonococcus or HIV, they actually may impair the ability of the organism to replicate, either in vitro or in the host. The first mutations make the organism uncomfortable, so when you take away the antibiotic pressure, for example in the midst of a new hospital outbreak, the resistant variants organisms may disappear. But eventually the organisms seem to develop compensatory mutations as they learn to survive in a new environment, not only under constant antibiotic pressure, but even after the antibiotic pressure is removed. For example, streptomycin resistance appeared in gonococci in the early 1950s to the level that nobody used streptomycin anymore because it was unreliable for gonorrhea. Yet if you look at gonococci today, you still find 20% are streptomycin resistant, even though nobody uses the drug for gonorrhea. So while it is probably true that there will be some devolution back to sensitivity, especially if the antibiotic pressure is withdrawn early, this may be less likely later.

Also, resistance to some types of antibiotics may have less effect on microbial growth and virulence than resistance to other types of antibiotics. Another interesting point is that when one type of genital organism first acquires genes that encode resistance to a particular antibiotic, it may transfer these resistance genes to completely different types of organisms in the genital tract. For example, tetracycline resistance was first discovered in Mycoplasma hominis, one of the genital Mycoplasma sp., and was due to the tet-M gene, which was probably transferred from streptococci into these genital organisms. This is just an indication that when you get one of these resistant strains into one bug, it does not necessarily stay in one bug. The tet-M also hopped into Ureaplasma urealyticum, Streptococcus agalactia, and Gardnerella vaginalis within a very short period of time, as well as Neisseria gonorrhoeae and Haemophilus ducreyi.

Readings

Holmes K. "Human ecology and behavior and sexually transmitted bacterial infections." Proceedings of National Academy of Sciences, 1994 March; 91: 2448-2455.

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