Presentation: Patient with Abnormal WBC Counts
Title: Pathology of AIDS
Date & Time: Wednesday, December 5, 2007 at 9 AM
Lecturer: Ed Friedlander MD
No quizbank for this unit. We usually think of good questions together at the end of the lecture.
|
|
|
|
HIV INFECTION ("AIDS", "acquired immunodeficiency syndrome", retroviral immunodeficiency, "slim disease", etc., etc.) pathology Arch. Path. Lab. Med. 114(3), Whole issue, March 1990 (still great); updates Disease-A-Month 44: 545, 1998; Ann. Int. Med. 134: 761 & 978, 2001; J. Allerg. Clin. Imm. 110: 3, 2002; molecular pathogenesis of the immunodeficiency Nat. Med. 9: 854, 2003.
Introduction
The anatomic pathology of HIV infection and its treatments are now well-characterized. However, the human side of the disease is still rapidly changing. I have tried to assemble a current overview of the published materials for you. If you can add to or correct anything in this handout, please do so, in class or after.
There are also a lot of obvious untruths being told about AIDS and related subjects. One reason that you study disease in medical school is so that you can help answer the public's questions about pop claims -- both those with some claim to legitimacy, and the rest. I have tried to help you do this, here and elsewhere.
The biopsychosocial aspects of AIDS and its related problems are very special and sensitive. It is hard for anyone, from whatever perspective, not to be upset and worried about AIDS! Again, if you disagree with anything I say about AIDS, please say so.
HIV infection covers a tremendous range of symptomatology, pathology, and pathophysiology.
Like syphilis
and lupus, you can say, "He or she who knows HIV, knows medicine". This lecture
will introduce terms and concepts that you will use for the rest of your lives.
The medical literature now refers to "commercial sex workers / CSW's / SW's" instead of "prostitutes". See JAMA 271: 196, 1994, Lancet 343: 86, 1994. I am not implying anything else by using this term. You also know already that not everybody engaging in this "work" is an adult and/or ever had a choice.
The term "MSM" or "men-who-have-sex-with-men" has replaced "gay / bisexual" in discussions of HIV transmission, which is simply common sense. It's what a man does or does not do, rather than what he thinks about himself, that determines his risk.
* For a minority-group-identity activist's objections
to the new terminology, see Am. J. Pub. Health 95: 1144, 2005.
I've concluded that these people are impossible to please.
AIDS, the full manifestation of HIV infection, is a devastating infectious disease that has been with us since the late 1970's.
The immunodeficiency is caused by damage to T-helper cells and dendritic macrophages by a recently-evolved retrovirus (human immunodeficiency virus, HIV, HIV-1; formerly HTLV-3/LAV) or its close relatives. Koch's postulates have been met, and a virulence gene (nef) located (today's final proof of etiology).
In AIDS, there is very little effective cellular immunity. A host of opportunistic infections occur until death eventually results.
By now, there is no honest doubt that HIV causes AIDS.
* Your patients and others will ask you, so here goes...
* The principal HIV-doubter (Peter Duesberg) is a former bench gene chemist who claims that AIDS is caused by homosexuality, drug abuse, and AZT. He uses the classic pseudoscientist's techniques of (1) mistaking unanswered questions for refutations, (2) groundlessly attacking the characters and motives of those doing honest research, and (3) telling some outright, obvious lies. See Science 241: 514 & 515, 1988; Nature 358: 13, 1992; Nature 362: 103, 1993; Lancet 341: 658, 1993; Br. Med. J. 312: 216, 1996 (anyone who wasn't born yesterday can recognize the obfuscation and special-pleading in his reply.) Or pull up his own stuff on Medline; it speaks for itself. There are a few other HIV doubters (a Nobel celebrity also known as an astrology proponent engages in some idle speculation: Nature 369: 434, 1994; more recently Jonathan Wells and Phillip E. Johnson, the two "intelligent design" movement leaders), but nobody with any medical or infectious disease qualifications.
* All the stuff that these people are directing toward the public nowadays is mud-slinging, conspiracy talk, character smears (including mine; I don't answer my crackpot mail), and claims of being persecuted geniuses. This alone assures me of what's really going on. Bunko artistry takes many forms, but is always directed toward the same basic human emotions -- the desire to believe ugly lies in order to feel intellectually and morally superior. You cannot reason with these people; don't get drawn into their game.
* Duesberg also claims that mutations do not cause cancer. His bizarre article in Proc. Nat. Acad. Sci. 97: 3236, 2000 is a fine example of the disinformation artist's technique of misrepresenting the information contained in the other scientific papers. In 2000-2001, one of our students (who said he "hadn't believed it could be as bad as Ed said, but it was") demonstrated this in lab as an alternative to a case presentation. Any takers this year?
* In 2000, President Mbeki of South Africa endorsed Duesberg's claims, and compared the scientific consensus about HIV to the vilest racial bigotry (Lancet 356: 225 & 1541, 2000; Nature Medicine 7: 1170, 2001; Br. Med. J. 321: 67, 2000; Br. Med. J. 323: 650, 2001; Nature 404: 907, 2000; Nature 406: 113, 2000; Nature 407: 280, 2000). In particular, Mbeki banned administration of HIV prophylaxis to pregnant women in his country to protect their unborn children, and as prophylaxis to women who have been raped (Br. Med. J. 318: 1507, 1999). The outcry from both scientists and humanitarians was massive and appropriate, especially at the World AIDS Conference in 2000. Yet Mbeki continued to stonewall until late 2002, when he was defeated in court. In 2001, half of Mbeki's expert panel, which he packed with Duesbergites, recommended garlic, ginsing, and music therapy instead of condom distribution (KC Star April 5, 2001). In August 2003, his people moved once again to ban nevirapine to prevent HIV transmission to newborns (Lancet 362: 451, 2003).
* Mbeki is a master politician and is surely not so naive as to really believe in Duesbergism or music therapy. Someone who is more cynical than I am would conclude the Mbeki just wants reduce the burden that surviving orphans place on his already-collapsing economy. Remember that 20% of South African adults are HIV-positive (5.3 million people total), there are 350,000 AIDS deaths per year, half the country lives below the poverty line (26th worst in the world), 37% of people are unemployed (17th worst in the world), rape is extremely common (a very bizarre and terrible feature of life in "the New South Africa" -- even the traditionally far-left-wing journal Soc. Sci. Med. 55: 1231, 2002 acknowledges this), and that AZT cuts the risk of transmission to the child from about 1 in 4 to about 1 in 12. Then do the arithmetic. A more favorable interpretation is that sly Mbeki is actually trying to draw attention to the need for medications in his country in order to get them donated. You decide. His outgoing health secretary, Dr. Mannto Tshabalala-Msimang, was much-ridiculed for her promotion of raw garlic and lemon peel for AIDS. More on the Mbeki government's overall massive indifference to the health of the citizens: NEJM 348: 750, 2003.
* HIV doubting is on the upswing, especially in Africa (Nat. Med. 11: 581, 2005). Of course, a few postmodernists have bought into it (Soc. Sci. Med. 58: 703, 2004 by a sociologist who says he cannot understand how scientific inquiry is different from religious dogmatizing.) Vitamin guru Matthias Rath even claimed to have the backing of the UN and international science groups (including "The Perth Group", evidently their own invention -- their rhetoric is based on "public debates" and "going to court", the traditional methods of disinformation artists.) The claim to support from the real scientific community is an obvious complete fabrication. See Nat. Med. 12: 369, 2006. There's no science here, but the politics is ripe: many people hate the companies that developed and market anti-HIV drugs, and anti-HIV activism plays to this.
* If you have any doubt that the HIV-doubters are bunko-artists and their dupes, consider this: There is also a large disinformation industry claiming that the HIV virus was bioengineered as a tool for genocide by the CIA, the apartheid regime, the vaccine companies, or whoever. If the Duesbergites believed their own stuff, they would attack these people, and be attacked in return, with the same venom that both campaigns reserve for honest science.
As a physician, society grants you status and special privileges, expecting in return that you will know and do whatever actually helps sick people. All beautiful rhetoric aside, you are betraying society's trust if you "keep an open mind" or "respect opposing views" from people who are obviously trying to deceive the public.
The virus is now widespread, but the disease is transmitted only by the most intimate contact or
sharing.
The principal features of AIDS are (1) vulnerability to infections by micro-organisms that
ordinarily do not produce severe disease
in humans (Pneumocystis and dozens of others), including pseudo-cancers that
are actually infections -- aggressive Kaposi's "sarcoma", less often B-cell lymphomas) and/or (2)
nervous system damage.
The disease attacks the brain, spinal cord, and peripheral nerves. Mild to severe nervous system damage often develops even in
the absence of immunodeficiency (for example, Arch. Path. Lab. Med. 114: 643, 1990).
A great deal is being written about possible mechanisms of nervous system
injury, but we still have many questions about how it really happens.
The most characteristic feature of HIV involvement of the nervous system
is giant cell encephalitis, the presence
of granuloma-type giant cells without classic granulomas. Probably
microglia (i.e., the brain macrophages) recognize the gp120 on each others' surfaces and this results in
their fusion.
www.AIDStruth.org
Real scientists organized
to debunk HIV doubters
{37378} HIV giant-cell encephalitis
|
|
In the early years, researchers distinguished stages of the disease, which mirrored how depleted the CD4 count was:
AIDS: Kaposi's or opportunistic infections
AIDS-related complex: milder opportunistic infections (remember cryptosporidiosis,
candida,
zoster)
Persistent generalized lymphadenopathy: just that;
Asymptomatic but immune-damaged carriers: just that;
Healthy carriers, i.e., normal immune systems. All of these people have the potential to transmit the virus.
The tendency nowadays is to treat all of these together as HIV-disease, and to base therapeutic protocols on the lab values.
* The late-1980's, early-1990's protocols for AIDS focused on CD4 counts ("Give anti-pneumocystis
prophylaxis if the CD4 count goes below 200": Ann. Int. Med. 111: 223, 1989; "Give zidovudine
when the CD4 counts drop below 500";
"but if you were asymptomatic, the side effects are as bad as the longer life
is good..." NEJM 330: 738, 1994; etc., etc.).
In 1996 we began to prognosticate AIDS by
quantitating the virus in the blood by PCR
(Science 272: 1167, 1996; J. Inf. Dis. 175: 576, 1997).
Today's assays can pick up 50 (or even fewer) copies/mL (Am. J. Clin. Path. 120:
268, 2003.)
And now we can also quantitate the HIV-1-specific cytotoxic T lymphocytes.
Not surprisingly, these counts correlate inversely with viral RNA
content (Science 279: 2103, 1998).
This is of great interest
to folks working on the AIDS vaccines, since these cells seem to offer
protection even though serum antibodies don't.
Probably a few people rid themselves of the established infection altogether (the baby, NEJM 332: 833, 1995), but it is very rare.
We know people survive exposure without infection, since many people with repeated exposure (CSW's, spouses of infected partners) have antibodies (typically mucosal ones) but no virus on board.
Some HIV-positive people present with, or remember, a brief, acute viral illness (the seroconversion phase) a few days following inoculation with the virus. There is a faint maculopapular ("little spots - little bumps") rash (* apoptosis of epidermal cells -- Am. J. Path. 126: 199, 1987), CD4 cells are greatly but briefly reduced (if you check) and the syndrome closely resembles infectious mononucleosis, with fever, malaise, adenopathy, and sore throat. It is extremely infectious. There is presently talk about treating this as a medical emergency, in the hopes of obtaining long-term viral suppression (Nature 407: 523, 2000) by a greatly-enhanced T-helper cells anti-gag response.
{05255} AIDS iceberg
{05256} AIDS iceberg
Until recently, HIV infection meant that you could expect to die from it. The new therapies are providing new hope, and more are on the horizon.
Most people who are found to be infected with HIV and are not treated effectively do progress to AIDS, with progressive drops in CD4 counts, over the following years, though the rate of progression is widely variable.
True non-progressive HIV occurs in around 5% of infected people (i.e., their CD4 counts remain normal, their lymphoid histology remains normal, and only tiny amounts of virus are found in their blood). Their immune response to HIV is better, and/or they are heterozygous for deficiency of the second receptor CCR5 (CKR5), and/or they harbor a genetically-crippled bug.
Many other people progress very slowly.
People who are able to mount antibodies against Tat have slow or no progression (J. Inf. Dis. 191: 1321, 2005).
Some people infected with virulent strains seem to mount a better T-cell mediated immune response against the virus than others do. Figuring out "why" will be difficult.
And there have been some strange findings recently. For example, coinfection with seemingly-innocuous GB virus C seems to slow the progression of the disease NEJM 345: 707 & 715, 2001; this is now clearly true: NEJM 350: 981, 2004.
By contrast, rapid progression is defined to be clinical AIDS within five years of infection. Especially, underclass status (IV drug use, other sexually transmitted diseases) has historically predicted faster progression, even where health-care access was the same as for the rich (Lancet 344: 1120, 1994). Before there was any medication for HIV infection, the average time between infection and the onset of AIDS was eight years: Science 240: 1333, 1988.
The HIV virus flourishes and multiplies, hidden within the cells of the immune system. How the virus accesses and takes over the cells: Nat. Med. 8: 673, 2002.
An untreated host turns over 20% of total-body HIV's per day. This is probably happening even during the "latent" period, deep in the tissues (Science 267: 483, 1995). When AIDS declares itself clinically, HIV redistributes itself throughout the body: Lancet 343: 383, 1995.
Originally, when AIDS had fully declared itself, death would follow in a few months (before zidovudine) to a few years (zidovudine-only era).
And of course, HIV-positive patients, regardless of how sick they are, can shed the infectious virus.
Infections
The combination of Kaposi's "sarcoma" and pneumocystosis in young MSM's led to the first recognition of AIDS in summer, 1981.
Pneumocystis carinii (now P. jirovecii) is a protozoan that had long been known to cause serious pneumonias (lung infections) in immunosuppressed people.
{37484} pneumocystosis (silver has stained these black)
Since then, many other opportunistic infectious complications of the prodrome and full-blown syndrome have been described. These include, but are not limited to:
Candida fungus infections
("yeast infections", "thrush"; very often affects the mucosal surfaces of
patients with AIDS and ARC)
Herpes simplex virus infections
(in AIDS patients, it's like an extensive full-thickness burn of the
epidermis, a necrotizing encephalitis, or a systemic disease.
{05272} herpes around the anus in AIDS
Cytomegalovirus infection (CMV,
a common infection in ordinary people; devastating in AIDS
victims, who get intractable colon problems,
lose their retinas, lungs, brain, etc., etc.) Diagnosis
of CMV encephalitis is now made by quantitating the CMV genomes
in spinal fluid (Neurology 50: 693, 1998).
* Until 1991, the Rx for CMV of the retina was lifelong ganciclovir, and you couldn't take this with AZT, so you chose between living six months with your eyes or twelve months blind. Foscarnet ("Foscavir") became available in the early 1990's, and could be be administered concurrently with zidovudine: Science 254: 1113, 1991. Intravenous cidofovir: Ann. Int. Med. 126: 257 & 264, 1997. Oral valganciclovir: NEJM 346: 1119, 2002.
Toxoplasmosis
(a protozoan infection; seldom serious in healthy people, but capable of destroying
the brain of an AIDS victim within hours. No, AIDS patients needn't get rid of their cats JAMA
269: 76, 1993.)
Tuberculosis: Arch. Path. Lab. Med. 124: 1267, 2000.
It's still very common, and likely to show itself in unusual ways,
getting missed clinically.
At the height of the epidemic,
around 10% of AIDS patients died with active TB> (NEJM 320: 545, 1989), and AIDS
patients were largely responsible for the dramatic increase in TB at the time (JAMA 261:
436, 1989). TB is the major health risk that a HIV-infected co-worker, classmate, cell-mate,
college roommate, etc., poses to healthy people -- and this is not a trivial concern! See Am. J. Med.
89: 451, 1990. Often the AIDS-patient's TB is a reactivation of one's earlier, mild infection,
yet it is also very contagious between AIDS patients (NEJM 326: 1514,
1992). You may see some granulomas despite the
poor immune function.
{42046} tuberculosis (the bugs are stained red)
Atypical mycobacterial infections (M. avium, M. intracellulare, and M. kansasii, which cause an
untreatable tuberculosis-like or diarrheal illness in AIDS patients; see Ann. Int. Med. 114: 366,
1991)
Histoplasmosis Cryptococcosis
Aspergillosis Nocardiosis Cryptosporidiosis and related isosporidiosis and microsporidiosis, protozoan infections.
First known
as veterinary pathogens, they infest the brush border of the gut, giving AIDS and ARC patients
intractable diarrhea.
{18817} cryptosporidiosis (the bugs stain pale blue and are in the brush border, see 'em?)
Other colonic infections include adenovirus "Hairy leukoplakia" -- masses of white warts on the tongue, caused by
Epstein-Barr Campylobacter -- a cause of diarrhea and sometimes sepsis.
HBLV / human herpes virus 6, which ordinarily causes a minor viral exanthem ("exanthem
subitem" / "roseola") and infects B-lymphocytes, attacks T-cells in the presence of HIV and might
greatly accelerate disease progression;
Lancet 343: 555 & 577, 1994.
It can also produce a fatal lung infection: Lancet 343: 577,
1994.
JC papovavirus, which causes progressive multifocal leukoencephalopathy, a brain disease
of the immunosuppressed.
Syphilis Rochalimaea, the bacillary angiomatosis / peliosis / cat scratch fever bug, acquired from cat
scratches (JAMA 269: 770, 1993; JAMA 271: 531, 1994).
Scabies, the common mite that gets the penis and finger-webs, is a grisly infection in AIDS
(South. Med. J. 87: 352, 1994).
Penicillium marneffei is an fungal opportunist in AIDS that
is coming to be recognized more often (Arch. Path. Lab. Med. 121: 798, 1997;
Arch. Path. Lab. Med. 128: 191, 2004), especially in Southeast Asia..
Trichophyton, pityrosporum, and some of the other trivial fungal infections of humans
become more troublesome in AIDS.
HTLV-I: causes myelopathy (Neurology 48: 13, 1997)
Herpes 8 Note that these are mostly intracellular parasites that require cell-mediated killing (because the
antibodies and neutrophils can't get to them). One infection
follows another, until one finally kills the patient.
Neutrophil function is also somewhat impaired in AIDS (though this is not the primary problem),
and bacterial infections can and do kill these people: J. Inf. Dis. 158: 627, 1989; kids are especially
vulnerable (NEJM 325: 73, 1991).
Kaposi's "sarcoma" (review NEJM 342(14), April 6, 2000.)
{05270} Kaposi's "sarcoma" in AIDS
Kaposi's "sarcoma" (in AIDS or not) is a pseudo-tumorous infection caused by a recently-discovered
herpes virus (KSHV / Herpes 8 * The individual bumps tend to be monoclonal and to exhibit some autocrine growth activity (Proc.
Nat. Acad. Sci. 94: 979, 1997).
KSHV carries a viral growth gene that interacts with cGMP system: Nature 385: 347,
1997.
This makes it "neoplastic" only
in the same sense that freckles are "tumors".
Kaposi's "sarcoma" features clusters of tiny apparent capillaries, without anaplasia (except perhaps
late), budding off normal blood vessels. Eventually, it grows as massed bundles of reticulin-wrapped spindle cells, with red
blood cells in slits between them. The dark pigment is hemosiderin.
In keeping with the etiology of a sexually-transmitted virus, around 40% of MSM's with AIDS will
eventually get Kaposi's "sarcoma", compared with only 10% of non-MSM AIDS patients.
In one study, around 40% of San Francisco MSM's have HHV-8 on board,
but none of 195 exclusively straight M's had it.
NEJM 338:948, 1998.
We'll learn later about epidemic Kaposi's in Africa's virus belt, where it travels without requiring the
help of the AIDS virus, and can remain stable or regress.
Of course, it is a chronic viral infection made worse by malnutrition
and other factors contributing to general ill-health.
And we'll learn about Kaposi's in
immunosuppressed transplant patients that remits when their immunosuppression is discontinued.
(Obviously it isn't and never was a real cancer.)
Malignant lymphomas (classic articles JAMA 261: 719, 1989; Am. J. Path. 138: 149, 1991; Hum. Path.
22: 659,
1991)
Malignant non-Hodgkin's lymphomas (mostly high-grade ones of B-cell origin) and microgliomas
are the other common AIDS-associated tumors.
Around 2% of AIDS patients get primary lymphoma of the brain. The diagnosis is made (if it's
made) by brain biopsy or autopsy, and the prognosis is dismal.
These lymphomas often show evidence of
Epstein-Barr virus Some of the lymphomas regress on HAART (Leukemia & Lymphoma 47: 750, 2006).
The others can be treated as they are in HIV-negative folks, so long
as retroviral therapy is continued, with about equally good
results as for HIV-negative folks (Leukemia & Lymphoma 47: 1822, 2006).
Hodgkin's disease in the AIDS patient: Update Am. J. Clin. Path. 121:
727, 2004. About 10% as common as non-Hodgkin's lymphomas.
Some of the AIDS lymphomas are
caused, instead, by KSHV (the Kaposi's virus; NEJM
332: 1186, 1995).
In keeping with the idea that these are virus-induced proliferations, and
in contrast to lymphomas in the immune-competent, many
(not all) are polyclonal (AIDS 8: 1025, 1994).
Nervous system damage (Arch. Neuro. 54: 846, 1997; South. Med. Assoc. J. 94:
266, 2001)
Many patients who are exposed to AIDS virus develop clinically obvious brain infection.
This is often severe and persistent, with loss of memory, inability to concentrate, apathy, and
eventually dementia. Around 50% of AIDS patients have clinically apparent mental changes. HIV-related emotional-behavioral
changes:
Am. J. Psych. 147: 696, 1990; this often
improves on HAART (Neurology 67: 311, 2006).
Around 90% of AIDS patients have some form of brain damage at autopsy. Maybe half have HIV
encephalitis, with multinucleated giant cells
and/or very aneuploid glia and/or microglial-macrophage nodule
formation (Classic articles Lancet 1: 309, 1989; Hum. Path. 22: 700, 1991), leading to substantial loss of brain
tissue.
{05309} AIDS, brain atrophy
gp120 is a neurotoxin, causing macrophages and
astrocytes to damage their neuronal neighbors (Nature 367: 113 & 188, 1994; Proc. Nat. Acad. Sci.
91: 494, 1994), very likely by
glutamate-calcium excitotoxicity (more about this in
CNS pathology). Obviously this is not the whole story, since the viral load
does not correlate well with the extent of brain damage.
* In transgenic mice, expression of tat is a potent neurotoxin (Am. J. Path. 162: 1693, 2003).
The conventional wisdom that early HIV infection usually
causes subtle brain damage seems not to be true:
Arch. Neuro. 54: 179, 1997; Neurology 48: 223, 1997.
Other forms of damage to the nervous system are common.
Chronic spinal cord involvement takes the form of "vacuolar
myelopathy", with ataxia and spastic paralysis; neuropathology in Neurology 58:
479, 2002. Guillain-Barré syndrome can happen during the infection.
Rarely, a viral meningitis occurs
during the acute infection. Review: West. J. Med. 160: 447, 1995.
Other Symptoms and Signs
Weight loss, more muscle than fat ("cachexia"), is usual in AIDS and ARC, and in the terminal stages is extreme.
This probably has something to do with cachectin (alpha-TNF), and levels of this monokine increase
in the serum as the disease gets worse.
Malabsorption, poor appetite, inflammation of muscle cells (visible on biopsy)
and muscle cell apoptosis also must play a role.
Complexes of the virus and its antibody coat the platelets, causing thrombocytopenia by a type III
immune mechanism.
gp120 is a B-cell superantigen and this may be why AIDS patients get
an increase in total immunoglobulin (J. Immuno. 161: 6681, 1998).
In some AIDS patients, the glomerular visceral epithelial cells swell and become detached from the
glomerular basement membrane. This results in heavy proteinuria ("nephrotic syndrome") and then
permanent renal shutdown (NEJM 316: 1062, 1987; NEJM 321: 625, 1989; Ann. Int. Med. 150:
287, 1990). For some reason this is much less common nowadays than it used to be.
* HIV synovitis: Br. Med. J. 300: 1239,
1990; Arthr. Rheum. 34: 257, 1991.
Seborrheic dermatitis may flare (Pityrosporum), and the hair may thin and/or turn gray.
Immunology
The first problem is that the virally-altered T4+ ("T-helper") lymphocyte in AIDS cannot recognize
and respond to soluble antigens (NEJM 313: 79 and 112, 1985).
This may be due to an intrinsic T4+ cell defect, binding of virus gp120 protein to the CD4 receptors
(seems most likely), or the result of the defective expression of HLA-DR on the dendritic
macrophages that must process and present soluble antigens to the T4+ cell.
Actually, the first cells in which HIV appears after exposure are typically
the dendritic macrophages, not the
T-cells. Remember that macrophages also express CD4, the major AIDS receptor, as well as CCR5 (the co-receptor
for the more commonly-transmitted strains of HIV).
A variety of expected T-helper cell responses are diminished or absent in infected cells.
You'll learn these in other courses.
The envelope proteins of HIV themselves have several toxic effects
on the natural killer (NK) cells as well (J. Imm. 176: 1107, 2006). The X4
subtype Interferes with function immediately; both major types eventually
cause apoptosis. This begins during the acute infection
(Blood 106: 3366, 2005).
The ability of the virus to establish itself is enhanced by T-cell activation by some concurrent infection.
A cell that is truly in G0 cannot be infected.
This probably explains why the disease is so much more easily transmitted to "fast-lane" MSM's
and IV drug abusers (who have lots of infections and thus lots of activated immune cells) than to accidentally exposed health care
personnel.
Soon, however, T4+ cells are greatly reduced in numbers as well as function.
You'll learn what we know of the molecular biology in your other courses.
In the weeks following infection, circulating CD4 cells drop to about half their normal levels, then
rebound.
The gp120 protein coats healthy T-cells, and the anti-gp120 antibodies
and T-cells angry with gp120 probably help destroy them.
Another likely mechanism for T-cell destruction is the interaction
between HIV g120 protein and the CXC chemokine receptor on the T-cell
surface; this appears to activate the lysosomal self-destruction program
(J. Clin. Inv. 116: 2078, 2006).
Even more striking and earlier changes in cell populations occur in lymphoid tissue (classic
papers: Arch. Pathol.
109: 128, 1985; Arch. Pathol. 109: 33, 1983).
Even surviving T4+ cells and macrophages don't respond to antigens very well, and make very little
interleukin 1, interleukin 2, gamma interferon, and so forth (Science 241: 573, 1988, more).
Part of the explanation is probably that viral gp120 (see below) plasters itself all over the CD4
proteins of T-cells and macrophages, rendering them ineffective.
Today many workers think that the last reservoir is phagocytized, non-integrated
viruses in the dendritic cells of the
germinal centers as being the reservoir. This will be hard to eradicate.
In any case, even in HAART-treated patients with excellent responses,
the deep lymphoid tissue is never normal even morphologically
(J. Inf. Dis. 186: 1092, 2002).
Patients almost all make
antibodies against HIV; however, these do not rid the body of infection. Of course, this is part of
why effective immunization will be so difficult.
The AIDS Virus ("HIV-1")
{00448} HIV
The etiologic retrovirus was discovered in 1984 (Science 224: 479, 1984, afterwards NEJM 311:
1292, 1984) and was named HTLV-3 (human T-lymphotropic virus-III).
* The French co-discoverers named their isolate "lymphadenopathy associated virus" (LAV). This is
the same virus.
The name was changed in 1986 to human immunodeficiency virus (HIV)
-- now it's HIV-1.
gp120 binds to (and inactivates) the CD4 receptor on the T-cell.
You know that retroviruses use reverse transcriptase to synthesize DNA from an RNA template
inside the infected cell. The DNA ("provirus") is then used to make more viruses.
Because reverse transcription is not very accurate,
HIV changes its genotype during
the infection. This is why it's so important not to miss a dose of
combination drug therapy for fear of the emergence of a resistant strain.
First transmission of a drug-resistant strain from a noncompliant
patient:
NEJM 399: 307, 1998. This is now common (NEJM 347: 385, 2002).
AIDS virus is closely related phylogenetically to retroviruses in other primates, including macaques, mandrills, and
African green monkeys. These are the various SIV viruses ("S" for "simian").
The darwinian lineage of the SIV family has been studied in depth. It is now clear
that HIV is a
simian infection that was transferred to human beings, and that this is the explanation for the
sporadic cases that preceded the epidemic.
HIV-1 was SIVcpz transferred
from
chimpanzees, at least three separate times, in East
Africa (Nature 397: 436, 1999).
HIV-2 was SIV transferred from a sooty mangabey monkey in West Africa
(Science 287: 607, 2000).
The AIDS virus became established in human beings
just before 1973, as antibodies against it are found in African human sera stored during that
year.
There were sporadic cases even earlier.
Since AIDS is a zoonosis, this is not surprising: Science 287: 607, 2000.
Of course, aggressive Kaposi's "sarcoma" has been recognized in Africa for several decades, and is
seen even in HIV-negative patients (yeah, we knew it wasn't a tumor all along).
* The Manchester seaman who died in England in 1959 "of AIDS" didn't.
It was a hoax; tissue chunks from two
different people were in the bucket (Nature 374: 503, 1995;
Lancet 148: 1363, 1996).
New strains of the virus are appearing.
The virus often changes its capsid, producing different strains even in the same patient. This is
another reason that it will be hard to develop a vaccine.
HIV-2 is a second virus that also causes AIDS (Nature 326: 662, 1987; NEJM 316: 1180, 1987;
the disease Ann. Int. Med. 118: 211, 1993). HIV-2 patients usually have healthy CD4 counts, at least for many years,
and many of these CD4+ cells
react against HIV-2; this is now thought to be why the disease
progresses more slowly. See J. Imm. 176: 6973, 2006.
HIV-2 also evolves more slowly within its host than does HIV-1 (J. Inf. Dis. 195:
726, 2007).
* HIV-1 Subtype O ("outlier") arose just past the
HIV1-HIV2 evolutionary node. Pre-1995 screening tests may have missed it. See J. Virol. 68:
1581, 1994; Lancet 343: 1333 & 1393, 1994.
* Yet another highly divergent subtype-N strain (YBF 30): Nat. Med. 4:
1032, 1998. Detecting it is not a problem: J. Clin. Micro. 39: 1379, 2001.
The CD4 ( OKT4, "T4") antigen itself is the receptor for HIV (Nature 312: 763, 1984). It
combines with gp120 protein of the virus).
Remember that it is the CD4 antigen that interacts with the HLA-DR antigens of the dendritic
macrophages in antigen recognition (Nature 328: 626, 1987); the antigen is also present on
dendritic macrophages.
Second receptor: An additional protein, either
CCR5
or CXCR4, must also be present on the cell surface to allow
most HIV RNA's to enter the host cell (Nature 381: 647, 1996). Homozygotes who lack the protein
are immune to infection with the common (CCR5-tropic / macrophage-tropic) strains of HIV
(Science 273: 1856, 1996),
and heterozygotes have non-progressive
HIV infection. Molecules: Lancet 351:
14, 1998. CXCR4 is more abundant on T-cells,
while CCR5's are more abundant on macrophages and neurons.
The R5 strains of HIV smolder more in
neurons
and macrophages, which express
lots of CCR5 (Am. J. Path. 152: 167, 1998). Nobody really
understands why (Nat. Med. 5: 303 & 344, 1999.)
The fact that the CCR5 strains are more common than the CXCR4 strains
suggests to me that the cells that are usually infected first in a new infection
are the dendritic macrophages.
* All about CCR5: JAMA 296: 815, 2006.
Most transmission is of strains that are strongly trophic
for macrophages, i.e., the R5's. Over time in an individual
patient, strains that are
cytolytic for T-cells emerge. These are called X4, CXCR4-using, or T-tropic,
and this "phenotype switch" causes the immunodeficiency to
become worse (Nat. Med. 4: 346, 1998).
* Yet another co-receptor, CX3CR1, when mutated, causes ultra-rapid progression of the
disease: Science 287: 2274, 2000.
* The proteins CCR3 and CCR5 are co-receptors for brain glia
(Nature 385: 645, 1997).
* The one consistently-identified HLA MCH Class I polymorphism affecting the rate
of the progression, a single amino-acid substitution,
is reviewed in NEJM 344: 1668, 2001.
Once the virus has gotten into one T-cell
or dendritic macrophage,
it can be transmitted to many more by direct transfer --
thus hiding from antibodies in the interstitial fluid.
Actually getting a viral-laden
lymphocyte from one person into another person's
bloodstream is evidently the
most efficient way of transmitting the infection, which explains a lot about the
epidemiology (JAMA 259: 3037, 1988). The naked virus has only limited ability to infect a new
person; it works much better if it's carried in a live T-cell that then meets another's T-cell.
Duesberg notwithstanding, you can find HIV in everybody (that means everybody)
with clinical HIV-type disease if
you search for it. "HIV-negative AIDS" is clearly something different.
In 1992,
we discovered patients in whom
HIV could not be
demonstrated by any means (including PCR),
but who have progressive loss of CD4+ T-cells
and sometimes opportunistic infections and/or AIDS-type quasi-cancers.
Four separate institutions agreed that it existed, but found no
evidence of a new immunosuppressive infectious disease: NEJM 328: 373, 380, 386 & 393, 1993.
Today "idiopathic CD4+ T-cell lymphopenia" is defined as CD4 counts under 300,
or less than 20% of lymphocytes. It remains a minor mystery; there have been a few
deaths caused by the immunosuppression,
but most patients are asymptomatic.
See J. Clin. Invest. 97: 672, 1996; J. Amer. Acad. Derm. 46: 779, 2002.
It cannot be AIDS, since there's no
nervous system disease apart from the opportunistic infections.
And it is probably not an infection, since allogenic bone marrow transplantation
is curative: Bone Marrow Tr. 18: 813, 1996. I believe it is most often
the result of T-cell-mediated autoimmunity against one's own CD4 cells.
ARC ("AIDS-related complex") -- still a useful distinction
Under the old nomenclature, unexplained fever, weight loss, diarrhea, fatigue, night sweats of
greater than three month's duration, in a person with evidence of HIV infection is called
AIDS-related complex (ARC).
Often patients with ARC are troubled with minor infections, especially
candidiasis Anatomic pathology of HIV infection
You will learn what the various infections and lymphomas look like in AIDS soon enough, and
Kaposi's "sarcoma" has been described above.
Even in the absence of infections or cancer, AIDS victims suffer profound depletion of their
lymphoid tissues, and also generalized wasting of body tissues, especially muscle (cachexia).
{23350} AIDS, atrophy of lymphoid tissue (trust me
that this was a lymph node)
In some tissues, patches of cells may be found undergoing apoptosis, usually a marker for
cell-mediated cytolysis. (See Am. J. Surg. Path. 10: 531, 1986.) For the original autopsy series of AIDS victims, read Arch. Pathol. 109: 737, 1985, Lancet 2: 85, 1988.
For the most recent large series, see Arch. Path. Lab. Med. 126: 182, 2002.
Taiwan's pathologists document that autopsy remains the gold standard,
and that opportunitstic infections are often missed in life (J. Micro. 39:
310, 2006).
The
usual precautions in handling tissues seem to protect pathologists and pathology students against
AIDS.
{20228} end-stage lymph node, AIDS; this used to be a lymph node, but almost all the lymphocytes
are gone
The lymphadenopathy of ARC and persistent generalized lymphadenopathy resembles that of other
viral diseases.
There is florid hyperplasia of the germinal centers, and other nonspecific reactive changes in the
nodes (debris, new vessels, etc., etc. -- Am. J. Surg. Path. 11: 94, 1987).
HIV testing
Growing the virus is difficult, PCR is costly, and the usual lab screen is to look for anti-HIV antibodies
in the blood.
The "screening test" is an ELISA ("enzyme-linked immunosorbent assay") procedure; it's usually
positive by 6-8 weeks, but can take as long as 6 months or even longer.
Today's ELISA's detect both p24 and HIV-1 (including subtype O)
and HIV-2.
"Positives" are confirmed
using a "Western blot" procedure and PCR.
Uncle Sam tests his army for HIV for only $2.50 per soldier (not bad, NEJM 32: 963,
1995).
Beware: Rare AIDS patients never seroconvert (J. Inf. Dis. 175: 955, 1997).
Blood banks, of course, do PCR on all units.
Think about just ordering a PCR if you suspect the acute HIV infection syndrome.
The virus is usually demonstrable in the blood in about 7 days after exposure,
and peaks at 3 weeks (NEJM 356: 2073, 2007).
Probably it is good public health policy to include PCR testing in ALL
HIV screening, at least those at high risk, since you'll pick up the
4% that are antibody-negative (mostly the acute infections, which are very
contagious: NEJM 352: 1873, 2005; there are rare false-positive PCR's).
Today, anonymous testing is widely available, and as a result, people are getting
diagnosed much earlier (JAMA 280: 1416, 1998).
Mail-in home HIV test uses a blood spot. It's remarkably accurate: Br. Med. J. 312: 1317, 1996;
Arch. Int. Med. 157: 309, 1997. OraSure (mouth juice) HIV assay: JAMA 277: 254, 1997.
Because of the benefits of HAART, started early,
perhaps it's a good idea to ELISA everybody who's not abstinent or in a
stable monogamous relationship every 3-5 years (NEJM 352: 586, 2005).
More on this hard-to-answer topic: Ann. Int. Med. 145: 797, 2006.
At risk
AIDS spread in the same populations as hepatitis B did in the mid-20th century.
Everyone remembers the four H's:
"Homosexual men" (MSM's): Haitians:
As noted before, the virus first infected humans in Africa. HIV and AIDS abound in sub-Saharan
Africa, in the "virus belt". See Science 226: 453, 1984. The African virus was probably acquired
there by Haitian "migrant workers". American MSM's brought the infection to the US from Haiti
("Patient Zero" was the most famous, but there were many others).
The explanation for AIDS among the little Haitian boys given in Ann. Int. Med. 99: 877, 1984 (they
were sex slaves... er, CSW's), has been quietly and generally accepted. Other infected Haitians received
injections through unsterilized needles in a folk medical practice. Haitians without other risk factors
are no longer considered a special risk group.
Update on HIV in Haiti: Science 313: 470, 2006 ("making headway under
hellacious circumstances")
Heroin (and other recreational intravenous drug) users:
In some populations, as many as 64% of IV drug abusers (men and women) are now HIV positive
(Br. Med. J. 300: 209, 1990). The statistics for New York City (JAMA 271: 191, 1994;
the most recent I could find)
stayed constant at around 50% during the peak years (ouch!), despite a shift from
injecting to snorting heroin.
Blood on shared syringes readily transmits the virus. Users can prevent infection by rinsing syringes
in hypochlorite ("Clorox") solution before sharing (unfortunately, this spoils rubber syringes).
Needle-exchange programs, where they have been implemented,
represent a new twist in the "war on drugs".
Politicians in the US mostly refuse
to fund these (Lancet 349: 604, 1997; Am. J. Pub. Health. 90: 1385, 2000).
On the "plus" side, they save money by preventing AIDS.
And they don't seem to increase the amount of drug use (JAMA
271: 115, 1994) or crime (Am. J. Pub. Health. 90:
1933, 2000). On the "minus" side, politicians would
be accused by their traditionally-minded constituents
of endorsing drug abuse. Nobody wants the needle-exchange boutique
next door (no kidding! Pub. Health. Reports 114: 439, 1999). Since intravenous
drug abusers are not a popular group,
there may be even darker reasons for voting down needle-exchange programs.
Finally, even if the government doesn't fund these programs, they'll still exist.
Most are non-funded and run by private donations;
about half are frankly illegal and are either tolerated or underground
(Am. J. Pub. Health 89: 43 1999).
Vancouver now provides its junkies with a medically-supervised
"safer injecting facility", without any obvious adverse impact
on the community (CMAJ 175: 1399, 2006).
IV drug abuse, and sex with IV drug abusers, is
was the most common way in which HIV is was
transmitted in the U.S. during the 1990's (Neuro. Clin. 11: 605, 1993, others),
and probably still is today, though the reappearance of the high-risk gay lifestyles has
shifted the numbers back toward transmission by anal sex.
Hemophiliacs
Around 85% of patients with classic hemophilia (who received human-derived
factor VIII) and hemophilia B (who
receive factor IX) were positive in 1985 (Ann. Int. Med. 102: 753, 1985; Am. J. Med. 80: 345,
1986; NEJM 317: 1153, 1987). One percent of cases of AIDS have occurred in hemophiliacs.
Others at risk:
AIDS is a special risk for infants of HIV-positive mothers. The virus crosses the placenta, and may
also be transmitted in milk. Review NEJM 332: 298, 1995.
Around 1.5% of U.S. women of childbearing age are now HIV-positive (JAMA 265: 1704, 1991).
In 1990, 782
babies were born with HIV. Without prophylaxis, the risk of transmission to the baby
is about 25%.
The new drugs clearly help prevent transmission to the
unborn child, and there are now laws requiring mothers-to-be to accept treatment.
The new statistics show that
AZT given to the pregnant mother cuts the rate of transmission from 19% to 3%
(Br. Med. J. 324: 381, 2002).
Mothers can now be forced by law to comply, which upsets
some people ("A woman's right to control her own body!")
but not me. You, the physician, had better offer HIV tests
to all pregnant women, but you had better NOT test
if she refuses (Am. J. Ob. Gyn. 180: 259, 1999).
Prolonged rupture of the membranes (more than four hours) is, not surprisingly, a major risk: NEJM
334: 1617, 1996. C-sectioning HIV-positive moms seems to cut the risk in half: Lancet 343: 1464,
1994.
We now know that breast-feeding is indeed an efficient way of transmitting HIV: NEJM 325: 593,
1991. Providing formula instead results in a huge reduction in
transmission: JAMA 283: 1167, 2000. Anti-HIV IgA is likely to be present in milk; it does not protect
the child (J. Ped. 149: 611, 2006).
In the poor nations, breast milk is clearly the best available food for newborns,
both from the standpoint of nutrition and protection from infectious disease.
Public health policy must weigh the 5-15% risk of the baby acquiring Mother's HIV
infections against this fact.
The ongoing complexities are shown by the observation that
non-breast-fed children in Botswana, while less likely to be infected
with HIV, are more likely to die overall, simply because of malnutrition (JAMA 296:
794, 2006).
HIV-infected children typically become symptomatic within a year (NEJM 321: 1791, 1989),
though some may remain healthy up to ten years. Around half of these children (who now number
in the thousands) have obvious brain damage (NEJM 319: 889, 1988), and they are also at
increased risk for bacterial infections (pneumococcus, H.'flu, salmonella, others) and the more
traditional AIDS pathogens. AIDS in children: J. Pediatrics 114: 1, 1989.
Also at (relatively low) risk are female partners of infected men. This includes wives and
CSW's.
As AIDS turns into a straight's disease
(Am. J. Med. 102 S4A:
2, 1997), CSW's are important vectors of AIDS in the poor
nations. In late-20th-century Thailand,
an "economic miracle" was driven largely by government promotion
of sexual services not available elsewhere,
and the night-life was dominated by unhygienic,
uncircumcised, lascivious young men. Most of the CSW's were
HIV-positive, and at least 12% of
the young men (especially the unhygienic, uncircumcised, lascivious ones) were infected (Lancet 343:
86, 1994; they catch it easily Lancet 343: 204, 1994).
Thai men wise up and start using condoms to
prevent HIV infection: NEJM 335: 297, 1996.
Promoting condoms to the
CSW's at the sexually-transmitted disease clinic in Zaire: Lancet 344: 246, 1994 (it helps).
Likewise, in America's crack houses, teenaged girls CSW themselves for drugs; 40% of these
girls are HIV-positive (NEJM 331: 1422, 1994).
By contrast, English CSW's are almost all HIV-negative, and their customers (though not their
boyfriends) use condoms regularly (Br. Med. J. 307: 356, 1993).
The same is now true for CSW's throughout Western Europe, though CSW's
coming to the area from the former Soviet bloc are likely to be HIV-positive because of
needle drug use (Lancet 364: 1, 2004).
In the early days, one percent of AIDS cases were acquired by blood transfusions (JAMA 254: 770,
1985; perhaps 12,000 people were infected by transfusions before testing made the blood supply
safe). If a person gets a unit of infected blood, the chance of contracting AIDS is around 95%.
* Hundreds of Americans were injected with material containing AIDS virus as part of the quack
Bahamas cancer treatment (JAMA 254: 1139, 1985; JAMA 255: 505, 1986). AIDS from sloppy
acupuncture technique: NEJM 320: 250 & 321: 1476, 1989.
* Thousands of Romanian infants were infected from moronic blood transfusions: Lancet 335: 595,
1990; Lancet 338: 645, 1991. Under the Ceausescu tyranny,
physicians had few things that they could do, so they gave
blood transfusions promiscuously.
The situation in sub-Saharan Africa is still a nightmare, but there are some hopeful developments.
Update: Lancet 364: 1, 2004.
AIDS is the major cause of young
adult mortality throughout much of Africa (Sci Am. 282(5): 96, May 2000).
For inspiration, see the account in Acad. Med. 82: 812, 2007.
Indiana Med partners with Kenya's medical schools to set up an effective
AIDS prevention and treatment program.
In sub-Saharan Africa, sexual promiscuity of any sort is a risk factor.
Explanations that have been put forward...
(1) Needles used in VD clinics and hospitals are not sterilized between patients (Lancet 2: 1018, 1985).
Unsafe
medical injections caused outbreaks among children in Russia in 1988 and in Libya
in 1998 (Int. J. STD 13: 152, 2002). Libya's response to
this embarrassing revelation was to charge 5 Bulgarian nurses and a Palestinian
physician with doing this intentionally. The Libyan government obtained confessions
by torture, and condemned the six to death; they were freed in 2007
after Bulgaria paid extortion money to Ghadaffi.
I am not making this up (Nature 430: 277, 2004;
Br. Med. J. 328: 1153, 2004; Science 308: 184, 2005).
Although the six health care workers were obviously innocent victims of
Gaddafi's evil,
even the WHO is now starting to talk
about the likelihood that iatrogenically-spread HIV is common in Africa
(Bull. WHO 80: 859, 2002; South Afr. Med. J. 94: 109, 2004).
In 2003, an activist popularized the notion that this is
more important than sex, and even if this doesn't seem to be so,
it's probably still happening at least sometimes (Nat. Med. 10: 44, 2004).
The militant claim examined: Lancet 363: 82, 2004.
(2) Heterosexual anal intercourse is widely practiced here
(Contraception Fertility & Sexuality 21: 145, 1993 -- the Paris-based
African Medical Institute, Am. J. Epidem. 135: 593, 1992),
both as a method of cheap birth control and
because many cultures practice "female circumcision" (more about this later), causing fibrosis so
that intromission is difficult;
(3) Other venereal diseases, with genital ulcers, notably chancroid, are
prevalent here (a risk for both men and women: J. Inf. Dis. 163: 233, 1991; Arch. Int. Med. 154:
1391, 1994).
(4) The "AIDS belt" (see below), where 10% or more of adults are
infected, corresponds very closely to the areas where men are uncircumcised: Sci. Am. 274(3): 62,
March 1996. In northwestern Africa, where most of the men are circumcised,
the HIV epidemic has been far less severe. In Senegal, the epidemic is
even described as "contained" (Lancet 364: 1, 2004; perhaps the fact
that this might be the best-governed country in the AIDS belt also gives people
hope for a better future and a reason to be careful).
Circumcision clearly protects a guy in the developed nations
from catching AIDS from a woman: Urol. Clin.
N.A. 22: 57, 1995; Arch. Int. Med. 154: 1391, 1994;
Lancet 354: 1813, 1999; Lancet 355: 926, 2000;
risk cut by 5/6 Lancet 363: 1039, 2004; Nat. Rev. Micro. 3: 914, 2005.
This seems to be fully accepted in today's medical literature,
and in fact, three African studies were stopped early for ethical
reasons because the benefits were so obvious (J. Sex. Med. 4: 838, 2007).
People are now talking about male circumcision being
the reason for the relative rarity of AIDS in Islamic countries (Repro. Fert. Dev. 13: 405, 2001 was first;
Lancet 364: 3, 2004).
A prospective randomized study of male circumcision in rural Uganda shows
about a 50% reduction, and not because circumcision changes behaviors
(Lancet 369: 657, 2007). Almost identical results from rural Kenya:
Lancet 369: 643, 2007.
WHO's chief HIV/AIDS director Kevin de Cock comes out strongly
in favor of circumcision to prevent AIDS: JAMA 297: 231, 2007 (* you
already know that's his real name).
* The anti-circumcision movement has, to date, countered with much inflammatory, militant
rhetoric but no counter-evidence; it would seem to me that they now bear the burden of proof, and
men in the AIDS belt are now lining up to be circumcised. (5) In much of Africa, the norm is "long-term concurrency" (i.e., a man has
several girlfriends, a woman has several boyfriends) rather than "serial monogamy" as in the United States.
Now, couples in "established relationships" don't always used condoms, here or there.
And sex evidently happens much more often between couples there than here. (Hmmmm...) See Lancet 362: 4, 2004.
"Transactional sex" (a new word for SW) seems to be driving the HIV epidemic
in Accra, Ghana (AIDS 18: 917, 2004).
One of the most disturbing features of the HIV epidemic in Africa
is that much of the transmission is through non-consensual sex.
Sexual violence against women as a major means of transmitting the AIDS virus in the changing
society of South Africa and its neighbors, where one woman is raped every 95 seconds:
Lancet 341: 1340, 1993 (read it; one new national leader says
that if a woman is raped, it is her own fault for going out of her house.)
Doctors describe the terrible prevalence
of rape and "coerced consensual sex" in "the new South Africa": Soc. Sci. Med. 55:
1231, 2002.
Another nightmare article: "Infect one, infect all -- Zulu youth response to the AIDS epidemic in South
Africa": A widespread, nihilistic
"youth culture" (i.e., vicious gangs)
actively seeks to infect everyone, especially by
raping women (Medical Anthropology 17:363, 1997).
Infant rape resulting from a folk belief that this cures HIV infection: Lancet 359:
274, 2002. Mbeki's government specifically reprimands a senior physician
for giving AZT to a baby who has been raped: Br. Med. J. 324: 191, 2002.
Whatever you decide is the underlying reason for this appalling business
(Br. Med. J. 326: 495, 2003 offers a politically-correct
analysis that I find altogether unpersuasive),
the same thing
is going on at comparable levels
in nearby countries as well where apartheid was never institutionalized.
It makes more sense to me to blame
misgovernment of whatever kind, with the resulting poverty, lawlessness,
and despair.
As the world rallies to provide antiretroviral therapy for Africa,
the drug companies have begun providing
regimens at almost no cost, and simplified
regimens seem to work (Am. J. Pub. Health 95: 1117, 2005).
* During the early years of the 21st century, the
factthat pharmaceutical companies weren't providing
free HAART for every AIDS victim in Africa was the subject
of a great deal of rhetoric.
Left out of the public
discussion was the kleptocratic tariffs, taxes, and regulations
imposed on these medicines (JAMA 286: 1996, 2001).
The World Health Organization's African branch has been
blasted by Lancet as totally ineffective because of
corruption and incompetence (Lancet 364: 475, 2004).
Outside financial aid to Africa from all sources
is only about $69 million annually (Lancet 357: 57, 2001); the world
is full of people who would like to help but know how hard it is to
help effectively given the bizarre politics.
Contrary to current fictionalized accounts ("The Constant Gardener"), the big
pharmaceutical companies do much less of the HIV research
in sub-Saharan Africa than do government and academics,
and there's actually disturbingly little work overall (Br. Med. J. 331:
742, 2005).
The world ridicules the Bush Administration's decision to
earmark a third of its $15 billion dollar contribution for
abstinence-only education: Nature 430: 279, 2004, many others.
For me, the most appalling thing about this is the fact that
many (most?) girls and women
in the poor nations cannot choose abstinence -- they are
forced into marriage, or if they do not get a boyfriend they will be raped.
For most poor girls in most of the poor nations, "violence and forced
intergenerational sex are the norm" (Lancet 364: 303, 2004).
This is a sad fact about our world about which we seldom hear in the US.
Further, all Bush-administration Federal money going to programs that offer condoms
has to include "education about the ineffectiveness of condoms".
I am not making this up. The Bush administration is of course
playing to its Far Right constituents, here as elsewhere (Nat. Med. 10: 759, 2004).
You'll have to decide whether it is good morals, but it's bad science.
How U.S. patients caught AIDS during the first decade (#'s rounded off, 1991 MMWR data):
59%: MSM's
100%
How U.S. patients are catching AIDS now (CDC online 2004)
100%
HIV infection in MSM's
As noted, AIDS first spread primarily among certain portions of the male "gay community".
Around half of identified, asymptomatic MSM's being followed by the CDC had
antibody to HIV in the mid-1980's.
Of course, the CDC study, and other like it, were of MSM's in selected populations, such as
venereal disease clinics. Obviously, members of longstanding "monogamous" partnerships are not
at risk.
Among MSM in epidemic areas, the geometric increase ended in the mid-1980's, almost entirely
due to people paying attention to the news, and the MSM community organizing and educating itself,
with no money from Uncle Sam. In San Francisco, the annual rate of new infection in MSM's
dropped to 1% in 1985 (Am. Med. News Jan. 24/31, 1986), and in Europe the prevalence of
antibody became stable (Br. Med. J. 298: 415, 1989). Unprotected "fast-lane" MSM lifestyles disappeared --
see JAMA 255: 171, 1986, Am J. Pub. Health 77: 578, 1987; Br. Med. J. 298: 215 & 218, 1989),
though some unsafe behavior persists (Am. J. Pub. Health. 81: 1321 & 1586, 1991, lots more).
In the early 1990's, safety was on everybody's mind,
and the rate of transmission dropped greatly
in the civilized world (Br. Med. J. 305: 561, 1992). Even among
young MSM's cruising in the public-meeting-places, only around 10% were
positive (JAMA 272: 449, 1994).
Even the people at Harvard, not noted for conservatism,
now talk about
"warning widely and spending wisely", and give free condoms to teens and
poor folks
(NEJM 331: 1451, 1994).
Disturbingly, there has been an upsurge in the gay community, perhaps because
of "complacency" or the expectation that the infection will be curable;
and today in the developed nations, about 44% of new infections
are transmitted by M's having S with M's (Lancet 364: 4, 2004).
Receptive anal intercourse is still the best predictor for seropositivity, especially if multiple partners
have been involved ( Am. J. Pub. Health 83: 79, 1993).
According to both the prospective San Francisco Men's Health Study (JAMA 257: 321, 1987), and
to a British study (Lancet 1: 345, 1987; also JAMA 255: 1703, 1986 and Br. Med. J. 294: 5,
1987), receptive anal intercourse is the only sexual practice that seems to transmit the epidemic
with much efficiency. Douching was an ancillary sex practice that contributed to risk, probably by
damaging the rectal mucosa. Fisting was also a likely risk factor. Ulcerative genital disease
(chlamydia Contrary to common-sense, insertive anal intercourse and swallowing semen or stool were not
demonstrable as risk factors in these studies. ("The absence of detectable risk for seroconversion
due to receptive oral-genital intercourse is striking" -- Lancet, above).
This was disputed only
anecdotally (Lancet 1: 1395, 1988; Lancet 338: 830, 1991)
until very recently, when 4 of 12 MSM's with
acute HIV infection supposedly had only unprotected oral sex as a risky
behavior (Ann. Int. Med. 125: 257, 1996) and monkeys
proved easy to infect by orally-administered virus (Science 272:
1421, 1996). In 1990, UCSF researchers who interviewed
newly-positive MSM's
reported that 8% said they got it from oral sex.
In Australia, self-reports disclose a high rate from oral sex: AIDS 17: 2269, 2003.
By contrast, UCSF researchers who actually sought out and tested
MSM's only engaging in oral sex found the risk to be "extremely low"
(AIDS 16: 2350, 2002); this disparity fits with previous work
and the not-so-surprising discovery that when you interview partners separately,
sexual histories are discordant (Am. J. Ep. 147: 1153, 1998).
* Chilling reading: the contemporary male CSW (Soc. Sci. Med. 32: 535, 1991)
providing CS for other men. About 1 in 6 is HIV-positive, many have wives or girlfriends (often
also CSW's), and surprisingly, most say that most of their customers are "straights" looking for
variety, and around 40% of customers are married. (This is confirmed in Arch. Sex. Behav. 21:
347, 1992). This sounds like an extremely dangerous thing for "straight men" and their wives, and
something physicians should know about. Male CSW's in this study were mostly teens looking for
extra spending money (Adolescence 27: 69, 1992). Los Angeles boys surviving on the streets by
giving sexual favors: Arch. Ped. Adol. Med. 149: 513, 1995.
* Amyl and butyl nitrites ("poppers", "pig pokers", others), used by MSM's having receptive anal
intercourse, were once rumored to be carcinogens for Kaposi's "sarcoma"; see Am. J. Med 78: 811,
1985; NEJM 317: 1603, 1987. This was simply wrong, but you'll still hear about this occasionally.
* For the best articles on male homosexuality,
see the online version of these notes.
Your lecturer believes that the scientific data, such as it is,
strongly supports the common-sense idea that most men,
regardless of "orientation",
are most interested in
friendship and macho-ness -- hard to find in our crazy society.
People NOT at great risk for AIDS:
The virus is very seldom transmitted except through sex or infusion of blood or blood products
(NEJM 314: 344 and 380, 1986; Hospital Practice June 15, 1986, p. 127; JAMA 255: 213, 1986;
JAMA 259: 1338, 1988).
People don't seem to get infected with HIV through casual contact with victims (in the home Ped.
85: 210, 1990; also South. Med. J. 82: 1071 & 1075, 1989 -- missionaries in
mosquito-ridden endemic areas almost
never get infected; Arch. Int. Med. 151: 1328, 1991 -- Peace Corps types aren't getting it by
"unusual routes", either). The virus does not multiply in the mosquito
and cannot get into the salivary glands.
The health institute in New Guinea actually looked
at this in depth and decided that you'd need to be btten by ten million mosquitoes,
each fresh from an AIDS patient, to be injected with a single HIV virus
(Papua New Guinea Med J. 39: 205, 1996).
It is apparently safe to share handshakes, hugs (WHEWWW!!!! -- Ed),
drinking glasses, toilets, classrooms, living quarters, and dialysis machines. (Dialysis was once
quite a concern; see
Ann. Int. Med. 104: 805, 1986; JAMA 225: 2324, 1986).
Health care workers routinely handling the blood and excretions of AIDS patients almost never
seroconvert (NEJM 314: 1127, 1985). People seldom seroconvert even after contaminated
needlesticks or knife cuts (maybe one HIV-positive needle-stick in 300; NEJM 312: 1, 1985;
Science 241: 161, 1988 -- but there have been a few cases).
The first (and so far only) conversion after an autopsy nick occurred
at Vanderbilt in 1997 (Arch. Path. Lab. Med. 121: 64, 1997).
Today, post-exposure prophylaxis for health-care workers is routine
and usually involves two anti-retrovirals (MMWR 50: 1-52, June 29, 2001).
With the advent of HAART, post-exposure prophylaxis
following needlesticks will need to be tailored to
the particular source (J. Infect. 43: 12, 2001).
Prophylaxis following rape is also routine.
No one knows quite how to handle requests for prophylaxis after other risky sexual
contacts (Emerg. Med. J. 18: 242, 2001).
Other transmission in the health-care setting is very rare (Ann. Int. Med.
104: 644, 1986; JAMA 259: 2817, 1988). Dentists aren't catching it, at least from drilling teeth
(NEJM 318: 86, 1988). Surgeons are inventing super-safe surgical techniques (Br. Med. J. 296: 80,
1988).
There is no documented case of AIDS being transmitted by a human bite (well, probably not: NEJM
332: 444, 1995). Nobody seems to be getting HIV from mosquito bites either, at least in the US.
People in Belle Glade, Florida, "who got AIDS from mosquitoes" didn't (Science 239: 193, 1988, not a pretty story).
* Sports for the HIV-positive: Med. Clin. N.A. 78: 377, 1994 (also includes everything that any of
you wanted to know about exercise-and-immunology, for what it's worth). The whole world has
talked about Greg Louganis's bleed into the swimming pool at the Olympics.
Heterosexual transmission:
Worldwide, this is probably the major means of transmission nowadays. But it is still less common
in the U.S. than some people had feared. Most regular heterosexual sex partners of infected people
have not seroconverted, though some do (Br. Med. J. 296: 526, 1988; NEJM 320: 183, 1989).
Your viral load determines how catching you are: NEJM 342:
921, 2000, others.
In the US, husbands and wives usually do not infect each other, even after many years (JAMA 259: 55, 1988;
Am. J. Med. 85: 472, 1988 -- risk factors for the woman seem to be anal intercourse, other sexually
transmitted diseases/genital ulcers, or if the man has full-brown AIDS, see Br. Med. J. 298: 411,
1989; confirmed at least in Uganda Lancet 357: 1149, 2001 & NEJM 342: 921, 2000).
In the US, most women who contract AIDS from sexual contact
do so from a bisexual or drug-injecting man, rather than a straight man.
And despite the ongoing
media concerns, there is clearly no self-sustaining AIDS epidemic in the entirely-straight
community (Lancet 341: 863, 1993). "Estimates of risks" for various situations: JAMA 259: 2428,
1988 (they made several assumptions....) Some of the work in the 1990's
confirms the low level of
transmissibility between straights in the rich nations, and the effectiveness of using condoms (NEJM
331: 341, 1994).
The main lab predictor for risk of infectivity is viral load; if there are fewer
than 1500 copies of HIV-1/mL, transmission is unlikely (NEJM 342:
921, 2000.) This common-sense observation
probably explains why (at least in Uganda) transmission
between heterosexual monogamous couples is most common during
the initial infection and at the end (J. Inf. Dis. 191:
1403, 2005).
Whatever the real rates, men seem to have much more difficulty catching AIDS from women than
vice-versa.
* One old army study "showed" that men are catching AIDS easily from women during normal sex -- a
finding that contradicts the good civilian studies. But the soldiers who reported "being with female
CSW's" may have simply diverted attention from practices that would at that time
have resulted in a
less-than-honorable discharge. See Ann. Int. Med. 104: 115, 1986; JAMA 254: 2094, 1985
(army); 254: 2599, 1985 (New York City, others).
Ulcerative genital disease (i.e., herpes In 1998 in these notes, I predicted the explosion in HIV deaths in India
during the following five years. About a third of a million people in India
will die of HIV this year (CIA figures).
The former Soviet bloc's epidemic is fueled largely by needle drug use
(Lancet 361: 1035, 2003).
China: Lancet 361: 2125, 2003 (in addition to the usual routes,
many people became positive from poorly-sterilized
needles at the plasma donor centers).
So far, evidence that lesbian practices can
transmit AIDS remain conspicuous by its
absence (Science 272: 1421, 1996).
Condoms:
Using a condom provides pretty good protection against infection (JAMA 255: 1706, 1986).
If a married couple uses condoms regularly, HIV
apparently doesn't get transmitted: NEJM 331: 331, 1994). The problem is getting people to use
them. See Science News 140: 141, 1991; the estimate that only 8% of sexually-active people have
more than one partner in a year seems low, but I'm not surprised by the report that only 1/3 of such
people use condoms even 50% of the time.
Safe sex: NEJM 316: 1139 1987. Surprisingly (?), many people who know they are HIV-positive
don't volunteer this information to those with whom they exchange body fluids (Am. J. Pub. Health.
81: 1586, 1991.) I doubt anyone was surprised by an article that people with
sexually-transmitted diseases continue to catch new ones even after solemn warnings (JAMA 267:
843, 1992).
* Catching AIDS from the dentist: MMWR 40: 21, 1991; evidence for transmission by a Florida
dentist looks pretty convincing (Science 255: 392, 1992; how the genetic stuff was done: Science
256: 1164, 1992). The remaining mystery is how HE transmitted it; he might even have
intentionally committed homicide.
There are six things that clearly reduce the transmission of AIDS.
* Health care teammates:
You will be exposed to a great deal of rhetoric about HIV and AIDS.
Keep this list in mind. Is the speaker merely grandstanding?
If not, what's the agenda? Men getting circumcised, expectant
mothers being
required to take anti-HIV medications, and new mothers not breast-feeding
are abhorrent to many on the Left. Condoms and needle-exchange
are abhorrent to many on the Right. You remember the
South African government banning prophylaxis for childbirth.
The last was simply politics-at-its worst, and I don't agree personally
with those who oppose any of the six interventions that work. However, you do not have
to support practices or policies that are contrary to your own moral
outlook. Simply be truthful with people.
Worldwide, about 57 million people have the HIV virus on board, and there
have been 22 million deaths (2002). There will be about 3 million deaths and 5 million
new infections this year. It's worst in the
"AIDS Belt". (The countries
are South Africa, Botswana, Zimbabwe, Malawi, Zambia, Tanzania, Burundi, Rwanda, Kenya, Uganda, and the
south half of the Sudan.)
* The impact of AIDS on world economies isn't the best way
to measure its human cost (J. Inf. Dis. 174 S2: S-253, 1996).
The author of this very interesting
paper suggests that the greatest impact of HIV is the
breakdown of social structures. In Rwanda, which may very well
have the highest percentage of HIV-positive young men, people
who saw themselves as having no hope for
the future may have seen no reason
not to lash out over ethnic grievances, causing the
longstanding race war to flare. I'd blame poverty,
kleptocracy, and overpopulation too, but AIDS is not helping.
* Of course, it's special pleading (i.e., untruthful)
to say that "HIV is the worst health disaster
that the world has ever experienced." Between 50 million and 100 million
people died in the influenza epidemic of 1918-1919, with millions
more permanently brain-damaged.
The black plague of the 1340's killed around 50 million people
in a much less populous world.
The die-off of the First Americans from disease after 1492 is hard
to estimate, but was probably comparable and certainly had a far
greater impact (Panminerva Medica 41: 78, 1999);
the impact of syphilis in Europe at the same time was also extraordinary.
Annual mortality from malaria, diarrhea, malnutrition, and obstetrical catastrophes
are all comparable / greater, and the historical death rate from measles
(around 750,000/year) has dropped only recently.
In mid-1989 the CDC counted its 100,000th case of AIDS in the U.S. (MMWR 38: 561, 1989),
and in December 1992, its 200,000th. There were about 90,000
new cases of AIDS in 1993, and this was
down to about 80,000 in 1994.
The death rate plummeted in 1996 with the advent of the new antiretroviral therapies.
Today, the rate of new infections in the US is probably around 40,000/year.
By the mid-1990's,
AIDS was the leading cause of death
in U.S. men ages 25-49. For women in this age range, who are less
likely to die overall,
AIDS was less common than accidents and in a near three-way tie with murder and suicide.
There are maybe 1.0 million HIV-positive people in the U.S., but nobody knows
for sure.
During the peak of the epidemic, two percent of
Manhattan residents presenting for military service were seropositive, 8% of San Francisco's
homeless were seropositive (JAMA 272: 455, 1994),
about 10% of young MSM's cruising in
California were seropositive (JAMA 272: 449, 1994, already cited),
and 0.2% of college students were
seropositive (NEJM 323: 1538, 1990). On the forensic autopsy service in the inner city, around 5%
were positive (J. For. Sci. 38: 1075, 1993).
The rates among intravenous drug users are clearly going down, both from die-off and from uninfected
people wising-up. For example, among needle drug users in NYC who get checked
at the methodone clinic, the detox clinic, or the STD clinic, seropositivity rates
are down by about 1/3 to 1/2 (Am. J. Pub. Health 88: 1801, 1998).
The infection rates in different cities are very different; about half of users
in Baltimore and Newark are HIV-positive, compared with only a few percent in Detroit and Denver
(sampling problem? see Am. J. Pub. Health 92: 385, 2002).
In 'Frisco,
only 12% of the needle users are now HIV positive (Am. J. Pub. Health 88: 108, 1998).
Castro had his version of the KGB administer his AIDS policy.
He tested everyone in Cuba for HIV, locked up victims and carriers, and expelled all infected
foreigners. Cuba now has a remarkably low prevalence of HIV.
Cuba's ongoing police-state approach, emphasizing surveillance and
quarantine of all infected persons, worked -- and is now drawing kudos
from the same people who, a few years before, would
have called it a "human rights violation":
West. J. Med. 163:139, 1995; still more praise
AIDS 17: N7, 2003. Today, the key feature is locking
up all new patients for a 6-8 week period of compulsory
education and treatment. Of course, with the collapse of the Soviet
Union, Castro's program has been funded by private donors, principally from the US,
who have ignored the embargo.
Up to half of young adults in some sub-Saharan countries may now be infected, and as we've
noted, the usual route is heterosexual intercourse.
AIDS care in apartheid-era South Africa was a fiasco: Lancet 342: 132, 1993. Because of the kleptocratic
governments, rank stupidity (i.e., reagents must remain un-refrigerated for days while passing
through customs), and "cultural factors", blood for transfusion in Africa was largely untested for HIV
until the mid-1990's; even afterwards, outdated kits failed to detect the virus
(Transfusion 37: 930, 1997).
There is some hopeful news. In the 1990's, Uganda stood
out from among its neighbors as being better-governed,
and its charismatic president launched an anti-HIV campaign,
jointly with Roman Catholic, Anglican, and Moslem leaders,
that could be a model for the rest of the developing world.
This was based around:
* Coercive testing of HIV-infected health-care personnel in the U.S. resulted from
demagoguery; the risks appear to be very small, though the fear is
understandable (Br. Med. J. 303: 325, 1991). HIV transmission (one way or the other) during
surgery is very uncommon, and avoiding AIDS transmission
is now a routinepart of good surgical
practice: Arch. Surg. 140: 961, 2005.
For the cost-benefit analysis of mandatory testing of physicians, see J. Fam. Pract. 38: 249,
1994; JAMA 271: 851, 1994. Thankfully, the business seems to be over.
* Major inaccuracies (lies) in the very popular book And the Band Played On, by an AIDS
activist-militant who accused physicians of willfully neglecting the problem during the early 1980's:
Science 239: 1039, 1988; Sci. Am. 259(4): 148, Oct. '88.
"The River: A Journey to the Source of HIV and AIDS" was a 1999 book
targeting Greens and making wild claim that the virus resulted from
the original work on the oral
poliovirus Blood banks screen all blood for antibodies against HIV I & II and p24
using ELISA;
in April 1996, we began testing each unit for HIV by PCR.
Donors have been asked about risk factors beginning in 1983.
Any M who has had S with any
other M during or after 1979 is excluded, any W who has had S with such a M, etc., etc.
Today, only one unit in 10,000 is positive for HIV-1 by Western Blot (they are discarded, of
course.)
Autologous transfusion, always a good idea, is now popular. Some people donate blood
to get the free AIDS test -- a practice that should be discouraged. The risk of a unit being infectious
was down to 2 in a million in the 1990's (NEJM 334: 1685, 1996);
the Red Cross's current estimate of risk
is still in this range (Ann. Med. 32: 469, 2002; one in 2 million
Lancet 361: 161, 2003).
There still seems to be a prevailing belief (several professional organizations and the Surgeon
General) that it is unethical for you, the student-physician, to refuse to place yourself at some risk in caring
for AIDS patients (Hastings Center Reports 21(2), 1991; Ann. Int. Med. 108: 464, 1988). A
thoughtful dissent by a medical student: JAMA 261: 1358, 1989. Your lecturer agrees with this
writer; beautiful rhetoric and beautiful ideology aside, the reality is that medical students are much
less skilled, and much more likely to stick themselves with contaminated needles.
Philosophers examine the issue of the HIV-positive physician in light of
other risks that we routinely accept: JAMA 267: 1368, 1992. The discussion in the literature seems to have ended.
Because of the stigma, legislation in some parts of our country once
made the confidentiality of a
positive HIV test absolute -- unlike the law for every other disease. In most jurisdictions, you have
to sign an informed consent to be tested for AIDS, and there's still a question as to whether I, as an
autopsy pathologist, can draw an AIDS test without the consent of the next-of-kin (!!) Much sillier,
in some jurisdictions, physicians have gotten into serious legal trouble for informing the wives of
AIDS carriers. The era of AIDS exceptionalism in this regard is over (Ann. Int. Med. 128: 759, 1998),
and "salus populi", the ancient common-law idea that protection of public health
overrides somebody's personal "rights", reigns again. "The other 'R'-word" ("responsibility") is now
printable; an AIDS militant talks about his duty to others ("After much thought...."; Br. Med. J. 312:
1083, 1996).
Abstinence has never been popular, but a siginificant minority of HIV-positive
people are abstinent by choice (past six months); interestingly, the 11% of MSM's usually
choose this out a sense of responsibility, while the 18% of MSW's (who of course were largely
intravenous drug users)
are mostly just too sick for loving (Am. J. Pub. Health 96: 1078, 2006).
AIDS prevention strategies emphasizing sexual ethics and
responsibility: NEJM 334: 1540, 1996.
The CDC provides funds for "counselling, testing, referral, and partner notification" (CTRPN)
for AIDS cases to states and cities. Assuming that this prevents one case of HIV infection for every
5 AIDS patients, it represents a cost-benefit ratio of 1:20; a good bargain (Arch. Int. Med. 153:
1225, 1993).
* In the early days,
AIDS victims -- especially children trying to attend school -- were
the targets of vicious
attacks. There is still a lot of crackpot rhetoric from both Right and Left,
which I trust you are able to recognize as such.
A social phenomenon without precedent during the 1980's
was the emergence of dozens of guerilla labs, which offered
"the latest experimental drugs" to all AIDS and ARC victims. It was in response
to a real need. And mostly
in response to AIDS, and to their credit, the FDA reversed
its time-honored practice of bureaucratically delaying the release of drugs. (Drugs were almost
always available for several years overseas before being released in the U.S., which was of course
the most effective way of testing their safety "and avoiding another thalidomide disaster".) This is
good news, and a rare triumph of common sense.
AIDS requires early intervention with costly therapeutic agents. And ironically, it increasingly
affects those least able to pay for care. The epidemic thus forces us to think more clearly about the
issue of health care as a right. We cannot resolve the question of what kind of health care should be
provided to patients with HIV infection if we do not also determine what care all citizens deserve
when they are ill.
-- Ronald Bayer, M.D., Columbia * The costs of treating HIV have always been high.
In 1996, the U.S. was paying for AIDS care at the rate of about $42 billion per year (Br. Med. J.
312: 466, 1996), which was about equal to the entire budget of Britain's socialized medicine system.
A Texas hospital founded in 1986 for
AIDS patients went broke in a matter of weeks. At the end of the 80's,
reported average costs ranged from
$27,000 (Arch. Int. Med. 148: 1793, 1988, cost-conscious center)
to $83,000 (Time magazine (Oct 16, 1989).
By the mid-1990's, costs were up farther.
Just before HAART, the cost was totaled to be $119,000 ($50,000 up to
the development of full-blown AIDS, $69,000 afterwards; JAMA 270: 474, 1993; the authors are
thankful that this represents a fall in costs due to a reduction in the use of inpatient hospital services;
similar data in Arch. Int. Med. 153: 219, 1993). In late-1998,
a RAND corporation study found we were paying only $6 billion per year
to treat the 231,000 HIV patients who are getting
care -- the triumph of managed care (NEJM 340: 1512,
1998). The patients are disproportionately poor (46% with annual
incomes less than $10,000/year) and black (33%).
In 2001, patients on highly-effective antiretroviral therapy
consumed an average of $18,000/year each (NEJM 344: 817, 2001).
By 2006, assuming a life-expectancy of just over 20 years for the average
AIDS patient starting HAART late in the course of infection, lifetime undiscounted cost of care is $385,200 dollars.
Seventy-five percent is the cost of medications (Med. Care 44:
990, 2006).
* Obviously, every dollar spent on AIDS care is diverted from something else, and AIDS obviously
diverts funds from other health care programs for the needy (JAMA 261: 378, 1989). In the
early years of the epidemic,
only a few people
had the chutzpa to talk about ethical problems involved in spending huge amounts of public
money on people who will all die in a few weeks anyway (Rev. Inf. Dis. 9: 1163, 1987; NEJM 314:
457, 1986; JAMA 261: 747, 1989 -- this illustrated the "law of inverse care", under which the
largest health care expenditures typically went to those least likely to derive much benefit.
Only after managed care struck did we start getting articles supporting
the common-sense idea (Ann. Int. Med. 128: 756, 1998).
AIDS militants at their peak:
NEJM 326: 128, 1992.
I cannot think that the street-theater era really helped improve the lives
of infected people, but
Bill Clinton packed his
"Office of AIDS Research" with
"responsible AIDS activists" (Nature 363: 391, 1993).
In 1989, the Feds established the National Commission on AIDS, a politicized body. Since then,
AIDS activists in Washington have shown considerable sophistication and common-sense.
"During 1997,
20-26% of all people living with HIV in the United States... passed through a
correctional facility" (Am. J. Pub. Health 92: 1789, 2002).
AIDS transmission in prison ("Well, shall
we give them condoms?..." Arch. Int. Med. 154: 739, 1994).
By now, every teenager knows what he/she must know about AIDS.
Even the JAMA (270: 725, 1993) isn't pushing for "more expenditures for AIDS education".
The WHO's 1994 decision to focus on "education" (i.e., spending money to tell people
what they already knew)
was heavily criticized as a terrible waste of precious funds
(Nature 369: 429, 1994).
Most "school-based programs to reduce sexual risk
behaviors" are total flops (Pub. Health. Reports 109: 339, 1994.)
Passive anal intercourse is the riskiest practice and
is commonplace even among "straight" teens (Arch. Ped. Ad. Med. 148: 1201, 1994);
for political reasons,
"AIDS educators" are sometimes not allowed to tell kids this extremely important fact.
There is a disturbing tendency to neglect the pain syndromes of HIV (BMJ 314: 23, 1997). And
right or wrong, physician-assisted suicide and active euthanasia were commonplace in many AIDS
practices (NEJM 336: 417, 1997 indicates around half of AIDS
physicians have granted a patient's specific request for a suicidal dose of opiates); so is ordinary
suicide (JAMA 268: 2066, 1992),
and around 10% of informal caregivers were comfortable telling
a stranger that they'd given drugs to speed death (Arch. Int. Med.
158: 69, 1998).
AIDS patients seek suicide when they can no longer care for themselves
or maintain their friendship systems (Lancet 358: 362, 2001).
As with cancer, it would seem to me that good terminal care
would reduce the demand for active euthanasia.
Caring for AIDS patients is stressful for caregivers, for obvious reasons. In addition to the fear of
contagion (i.e., TB Immunization
Because the virus changes so rapidly (even within individual patients), and because antibodies don't
protect well, finding a good vaccine will be difficult.
Updates Nat. Med. 9: 874, 2003; Nat. Med. 10: 221, 2004 (pessimism);
NEJM 356: 2073, 2007 (more pessimism).
An attempt in 1992 to obtain massive public funding for a quacky gp160-based vaccine was
defeated by a coalition of scientists and informed AIDS activists "who knew a con trick when they
saw one" (Nature 363: 39, 1993; I wish everybody did).
A "live attenuated strain" of SIV gave its monkey recipients lethal AIDS
(JAMA 280: 1211, 1998).
Despite the biological
and political difficulties (review JAMA 280:
1211, 1998), trials of AIDS vaccines have been
underway in some of the poor nations since the mid-1990's. So far,
all have been failures.
In 1998 VaxGen launched its trial of AIDSVAX, which is gp120 from two strains
of HIV on an aluminum adjuvant. The focus was in Thailand (why?) See
Lancet 351: 1789, 1998; Br. Med. J. 316: 1769, 1998.
By mid-1999, it has proved to be a major disappointment
(Nat. Med. 5: 612, 1999; J. Virol. 72;
1552, 1999), and today's talk is that perhaps human
beings simply cannot make neutralizing antibodies against HIV.
The latest vaccine failure (J. Inf. Dis. 191: 647, 2005)
was gp120-based.
It's now clear that the HIV vaccine tried in Thailand from 1995-1998 was
a total failure: J. Inf. Dis. 194: 1661, 2006.
I predict that the first successful AIDS vaccine will be poxvirus-based.
This is a popular
way to make T-cell-activating vaccines. A successful vaccine
in monkeys: Nat. Med. 5: 612, 1999.
A DNA vaccine
followed by a poxvirus carrying multiple retrovirus proteins: Science 291:
1879, 2001; Science 292: 69, 2001.
And now, a human canarypox HIV-1 vaccine: J. Immuno. 171: 1094, 2003.
It proved not good enough to continue trials: J. AIDS 44: 203, 2007.
* Please think for a moment about the politics of AIDS immunization
(JAMA 271: 295, 1994;
Science 272: 1880, 1996; both
good reading, full of things most of us never thought about).
Getting a U.S. company to invest in a vaccine will be even trickier, with the tort liability and the
reality that the people most likely to benefit are the ones least able to pay. Reality check.
Companies have a strong disincentive
to research-market vaccines, when the people who really
need it are mostly US drug abusers and poor people in the Third World
(90% of HIV infections are in the poor nations; 2/3 are
in Africa),
and when the company will
be harassed and threatened by everybody from the
street-theatre mudslingers to the tort lawyers.
Specific therapies for AIDS
We still do not know the long-long-term outlook, and this makes
clinical studies trickier (J. Inf. Dis. 177: 761, 1998).
Before 1999 there were whispers about "cure".... but
unfortunately, to date even people who have zero detectable HIV-RNA
in their bloodstream
still have the viral DNA in their tissues
and we're not going to be able to eliminate this with the current Rx's
(Proc. Nat. Acad. Sci. 94:
12574, 1997; Lancet 352: Supplement 4, 1998;
Nat. Med. 5: 609, 1999;
how it resists eradication Hosp. Pract. 33(9): 87, Sept. 15, 1998.
Of course, not everybody
adheres to the protocols (the mentally ill and the substance-abusers: Am. J. Med. 114: 573, 2003).
Today about 20% of new infections are by HIV strains with at least
one drug-resistance gene: Br. Med. J. 322: 1081, 2001.
In 1987, Congress passed the Ryan White Comprehensive AIDS Resources
Emergency (CARE) Act, providing zidovudine for those without other
access. States formed AIDS Drug Assistance Programs (ADAP's)
to deliver the goods. This is of course economic exceptionalism,
since heart patients, cancer patients, and so forth
do not have similar programs. And of course it is the result
of special-interest group pressures on legislators.
More on "justice", without facile answers: Ann. Int.
Med. 128: 758, 1998. Nowadays many ADAP's are
having to cap enrollments and/or refuse the new therapies
to their enrolees. If medicaid were to consider making HAART an entitlement,
we'd spend about $1.5 billion per year on it (Am. J. Pub. Health. 91:
1464, 2001; obviously the pricetag varies depending on how much
we allow the drug companies to charge); we'd also generate more drug-resistance and understandably
outrage
the working poor who still cannot get the medicines. Of course,
many people in the poor nations
do not have access to these lifesaving therapies:
Lancet 352: 1379, 1997 (the world notices). In 2004, the price of some of the HAART drugs dropped precipitously for some
reason. A fixed-combination of nucleoside and non-nucleoside reverse transcriptase
inhibitors cost only $250/year in 2004, and there was
immediate talk about making this
available to Africa's poor (Lancet 364: 3 & 29, 2004).
Now it's down to $140/year (generic; $560 for the proprietary: Nat. Med. 10: 1273, 2005).
The treatment programs using simplified HAART
are now underway (Doctors Without Borders in Malawi: Lancet 367: 1335, 2006), and even the governments
are key providers (good news from Zambia: JAMA 296:
782, 2006; JAMA 298: 1888, 2007)
or at least not interfering (South Africa's medical schoools:
Arch. Dis. Child. 92: 234, 2007).
Yes, there may
be resistance because of imperfect compliance, and this is the real
burning question.
So far, at least by self-report, compliance by Africa's poor is as good
or better than in the US: see JAMA 296: 679, 2006 and Lancet 368: 1587, 2006.
More AIDS drugs are in the works.
* And of course there will be more grave disappointments. Nonoxynol 9, the spermicide that supposedly also kills AIDS virus, as a 1:10 solution in vinegar, may be
applied to rape victims and will not interfere with evidence-gathering (JAMA 261: 3407, 1989) or
DNA analysis (J. For. Sci. 38: 442, 1993). The most recent evidence
is that the stuff is not useful in preventing the spread of AIDS:
AIDS 14: 85, 2000; this is not surprising since the most efficient
way to transmit AIDS is to inject an infected cell directly into the bloodstream,
bypassing any disinfectants. At this time, a mega-review from McMaster indicates exactly no
real evidence of the effectiveness of any "alternative / complementary"
remedy for AIDS, with the possible exception of some subjective relief
from common stress-management (Int. J. STD & AIDS 16: 395, 2005).
Pulmonary tuberculosis
Photo and mini-review
Brown U.
AIDS / CNS lymphoma /
Mycobacterium avium complex
Pittsburgh Pathology Cases
: a common fungus infection that is seldom serious in ordinary people; the agent
disseminates throughout the body of the AIDS victim.
Look for little two-micron yeasts.
:
infections with a fungus from pigeon droppings that can be rapidly lethal to an
AIDS victim, destroying brain, lungs, other organs. The fungus is a yeast that
has a capsule
and buds singly. See Arch. Path. Lab. Med. 110: 502, 1986, nice
pictures.
* A specific defect in HIV-positive T-helper cells prevents
them from responding to interleukins and becoming
able to directly kill cryptococci. Details are being worked out (Blood 109:
2039, 2007).
Cryptococcosis
Photo and mini-review
Brown U.
,
lung infection with the familiar fungus from high school biology (NEJM 324:
654, 1991)
,
the famous hard-to-treat, weakly-acid-fast filamentous
bacterium, is a still-not-well-known AIDS opportunist (J. Lab. Clin. Med. 145:
156, 2005).
and spirochetosis. Along with the better-known
Kaposi's, CMV,
cryptosporidiosis, and common bacteria, these cause the colonic
symptoms that are so troublesome for AIDS patients (small-volume diarrhea, tenesmus,
bright red blood per rectum). How to read a colon biopsy: Arch. Path. Lab. Med. 125:
1042, 2001.
(classic articles JAMA 259:
384, 1988; Am. J. Path. 139: 185, 1991.)
(notably neurosyphilis;
tougher to cure than in the non-HIV infected; see NEJM
331: 1469, 1994) and other curious bacteria (Rhodococcus: Can. J. Inf. Dis. 1: 101, 1990 by the
UMKC team; odd rickettsia NEJM 323: 1573, 1581 & 1625, 1990, etc., etc.).
Bartonellosis
Bacillary angiomatosis in AIDS
Yutaka Tsutsumi MD
/ HHV-8 / KSHV: a "tumor" virus ("Kaposi's sarcoma", lymphomas)
{05257} Kaposi's in AIDS
{32447} Kaposi's, foot
{32448} Kaposi's, ankle
{18816} Kaposi's, histology (weird vessels,
especially
notice the red cells between the spindle cells)
,
Science 267: 959, 1995; Lancet 345: 759 & 761, 1995; NEJM
332: 1181 & 1186, 1995; NEJM 336: 163, 1997) that arises multifocally as nodules of bizarre
vessels in the deep dermis. In AIDS (as well as in non-HIV-related African Kaposi's), it is
aggressive and infiltrates the guts, body cavities, lungs (Chest 117: 410 & 1128, 2000), etc.
All about Kaposi's: Med. Clin. N.A. 81: 471, 1997.
* Not surprisingly, with the disappearance of
the fast-lane gay lifestyles, transmission of the Kaposi's virus
is evidently way down. It is now quite uncommon even in advanced AIDS
(Cancer 100: 2644, 2004).
as etiologic agent (Medicine 70: 137,
1991) and/or myc activation. The brain lymphomas are always
Epstein-Barr related (Lancet 338:
969, 1991).
Damage to the peripheral nerves ranges
from asymptomatic changes to a chronic, crippling disorder.
There is both loss of myelin and loss of fibers (Neurology58: 115, 2002).
Pathologists see
Arch. Neuro. 61: 546, 2004.
What cells actually produce HIV particles during chronic infection? It's become clear
from following HAART patients that the drop in viral load follows four phases.
The largest drop occurs in a few days and reflects the contribution from T-helper cells.
The second drop probably reflects the slower control of production by dendritic macrophages.
It's not clear exactly how the third or fourth drops happen.
The bug is concentrated around Liberia and Sierra
Leone. HIV-2 AIDS is slower (T-cell count and anti-HIV T-cell
function are preserved: J. Imm. 176: 6973, 2006), less catching (Lancet 343: 943, 1994), and much less
common, but transmitted in the same ways, and equally lethal. We check donor blood for it, though
it's rare in the U.S. (JAMA 267: 2775, 1992).
HIV-negative AIDS
,
cryptosporidiosis, bad herpes
simplex and/or
zoster,
hairy leukoplakia, tinea pedis ("athlete's
foot"), tinea cruris ("crotch-rot"), others. Lymph nodes are usually enlarged.
{05258} AIDS cachexia
"Bystander apoptosis" is now well-studied, and seems to result from infected
T-cells with upregulated fas-ligand/CD95, which triggers the fas apoptosis trigger on the
surfaces of neighboring cells. This may well account for much of the wasting syndrome and
the destruction of uninfected T-cells (Virology 285: 181, 2001; AIDS 15: 957, 2001;
Clin. Exp . Imm. 122: 364, 2000, many others).
Since only about 70% of people in the US who are HIV-positive
know it (i.e., about a quarter-million don't know), offering to test is very important -- especially because
people who know they are positive supposedly will be more careful with others.
Early in the epidemic, this was the main US group affected, thanks to the
widespread practice of unprotected anal intercourse.
Today, around half of HIV-positive patient being treated are MSM.
See below.
21%: IV drug abusers
7%: MSM's who also do IV drugs
3%: heterosexual contacts of the above
3%: transfusions
1%: hemophiliacs
1%: from Mother
1%: overseas, in areas of "heterosexual transmission"
4%: ???
42%: MSM's
25%: IV drug abusers
33%: heterosexual contacts, mostly of the above
,
herpes)
also clearly increases risk (JAMA 260: 1429, 1988; Am. J. Pub. Health 81:
1576, 1991), and probably does for straight M's also.
,
syphilis,
and those others) seems to place a man at greater
risk; in one study, the only husband of an HIV-positive wife who
turned positive had frequent bleeding during intercourse (JAMA
266: 1664, 1991).
A tisket, A tasket / A condom or a casket....
-- Truck stop graffiti, 1991
Human aspects of AIDS (update NEJM 347: 357, 2002)
1. HIV testing of blood products for transfusion
2. Anti-retroviral prophylaxis before and during childbirth
3. Condom distribution and use
4. Needle exchange programs
5. Male circumcision
6. Formula feeding instead of breast feeding by HIV-positive mothers
Botswana and Swaziland are near-tied for the highest infection rate, with
around 38% of adults being positive (CIA 2004). For total numbers, South Africa
has the most (5.3 million, 2004 figures); India will soon catch up and pass this.
Condoms were also distributed, but a majority of youngsters reported not using them
because they were in monogamous relationships or abstinent.
HIV prevalence among the young
is actually dropping, and not just from die-off (this isn't
happening in Uganda's neighbors). See Lancet 360: 41, 2002.
Curiously, despite all the rejoicing you'll find little reference
to another factor that must be operating --
men in Uganda have been electing for circumcision,
which greatly reduces their ability to become infected from their
female partners (Am. J. Pub. Health 90: 1029, 2000;
NEJM 342: 921, 2000; NEJM 343: 364, 2000). Yet another factor:
the countries whose "public health policies are doing the most to
stop the spread of AIDS" are also (in my opinion) better-governed
(as evidenced by a growing GNP),
so that a young person may choose to live for a better future rather
than choose to throw his/her life away partying.
By contrast, the countries with the worst HIV growth
(South Africa most infamously) have collapsing economies.
vaccine.
The author, an anti-immunization militant, claimed that chimp tissues
were used in the development of the polio vaccine and that this is
the origin of AIDS. The people who actually did the work say
that chimp tissues were not used (Science 289: 1141, 2000).
And the claim was finally refuted simply by analyzing
some of the original material (Science 292: 743, 2001;
Nature 410: 1035 & 1045 & 1046 & 1047, 2001). It takes only
moments to make up a lie, a few minutes to disseminate it,
but years to refute it -- and doing the refutation merely makes
true-believers / suckers angry.
Hosp. Pract. Feb. 15, 1994
), the tremendous effort and expense, and
(until recently) the certainty of death, the physicians and nurses
who focus on AIDS care are also caught in the middle of society's debate about health care
rationing. Not surprisingly, burnout and "combat fatigue" are commonplace (Am. J. Psych. 150:
705, 1993). Palliative care for AIDS patients,
including comfort measures and handling the opportunistic
infections: Br. Med. J. 315:
1433, 1997.
Being infected with HIV, while still very serious, is no longer a death sentence.
This is due to the success of reverse transcriptase inhibitors combined with the anti-HIV-proteases
(saquinavir, etc.): Nature 374: 494, 1995, Lancet 345: 902, 1995; design-your-own (Proc. Nat.
Acad. Sci. 92: 3298, 1995); ritonavir NEJM 333: 1534, 1995. The triumph of the combination of
saquinavir, zidovudine, and zalcitabine: NEJM 334: 1011, 1996.
"HAART" (highly active anti-retroviral therapy)
renders HIV infection non-progressive, and can sometimes clear the
blood of the infectious agent.
Protease inhibitor review: JAMA
277: 145, 1997.
The protease inhibitors: Arch. Int. Med. 157:
951, 1997; NEJM 338: 1281, 1998.
Combination therapy Am. J. Med. 102: 76, 1997.
Review of the current successes (mortality cut by over 2/3):
NEJM 338: 853, 1998.
How T-cells repopulate when HAART
begins: Nat. Med. 4: 208, 1998.
People with private insurance are more likely to get the new
drugs than are people on welfare, and there has been amazingly
little outcry from militants over this -- perhaps they sense
changing public attitudes about entitlement.
* The
ethics of studying new vaccines and treatments on
poor people is complicated. Does a company merely
need to compensate its experimental subjects, as
in the US? (Yearly income in Tanzania is $90 per capita.)
Or
if you tested your new therapy or new vaccine
on a few thousand Africans, and it works, do you have a
moral, human-rights obligation to provide it
free to the entire impoverished continent
(Am. J. Pub. Health 88: 560, 1998)?
This raises unanswerable questions (at least in my mind)
about a "right to HAART" where
there is no certain access to economic or personal security,
basic health care, or even food. The often-told,
bitter joke is that if a glass
of pure water cured AIDS, Africa would not be able to afford it.
The first AIDS patient got his baboon bone marrow
transplant in 1995 after a great deal of strange politics.
The transplant itself was a flop
(Nature 339: 577, 1996; Lancet 347: 457, 1996).
AIDS
Pneumocystis carinii
Kaposi's sarcoma
Kaposi's sarcoma