Ed Friedlander, M.D., Pathologist

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.

First Section
Chaing Mi, Thailand

Second Section
Chaing Mi, Thailand

Immune Disease
Iowa Virtual Microscopy
Have fun

Text and pictures
From "Big Robbins"

AIDS in Africa
Time Magazine
Good text and photos

Neuropathology of HIV infection
Nice photos and article
Temple U.

AIDS in Asia
Time Magazine
Good text and photos

Pathology of HIV Infection
WebPath Tutorial

HIV itself
WebPath Tutorial

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.


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.

      The ability to mount an antibody response to a specific bacterial invader is also limited, but not so dramatically; total immunoglobulin levels are actually increased.

    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.
    Real scientists organized
    to debunk HIV doubters

    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.

{37378} HIV giant-cell encephalitis

HIV-induced encephalopathy

Yutaka Tsutsumi MD

AIDS and the brain
Uniformed Services

    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.

      The most famous case of a crippled HIV strains was one with mutated nef, from a MSM blood donor and the seven folks he infected, all originally thought to be true non-progressive. Three of the seven have undetectable virus levels; the remaining four have very slow immune deterioration (NEJM 340: 1715, 1999; also Sci. Am. 281: 22, July 1999.). * Nonprogressive viruses with mutated Vpr: J. Clin. Invest. 111: 1547, 2003.

      Many other people progress very slowly.

        One known factor that causes slow progression (but gives no protection against transmission) is certain alleles of the receptor protein CCR2: Nat. Med. 4: 350, 1998.

        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.

      Patients on the new therapy without measurable HIV in the blood are probably not shedding -- but don't let your guard down. (Or with any other patient.)


    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)

Photo and mini-review
Brown U.

Pneumocystis carinii
H&E, see the froth
KU Collection

    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)

Pulmonary tuberculosis
Photo and mini-review
Brown U.

      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)

AIDS primary effusion lymphoma
Good pictures

AIDS / CNS lymphoma /
Mycobacterium avium complex
Pittsburgh Pathology Cases

      Histoplasmosis: 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.

      Cryptococcosis: 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).

      Photo and mini-review
      Brown U.

      Aspergillosis, lung infection with the familiar fungus from high school biology (NEJM 324: 654, 1991)

      Nocardiosis, 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).

      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 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.

      "Hairy leukoplakia" -- masses of white warts on the tongue, caused by Epstein-Barr (classic articles JAMA 259: 384, 1988; Am. J. Path. 139: 185, 1991.)

      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 (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.).

      Rochalimaea, the bacillary angiomatosis / peliosis / cat scratch fever bug, acquired from cat scratches (JAMA 269: 770, 1993; JAMA 271: 531, 1994).

Bacillary angiomatosis in AIDS
Yutaka Tsutsumi MD

      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 / HHV-8 / KSHV: a "tumor" virus ("Kaposi's sarcoma", lymphomas)

    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
{05257} Kaposi's in AIDS
{32447} Kaposi's, foot

Kaposi's sarcoma in AIDS

Yutaka Tsutsumi MD

{32448} Kaposi's, ankle
{18816} Kaposi's, histology (weird vessels, especially notice the red cells between the spindle cells)

Kaposi's sarcoma
AIDS patient
KU Collection

Kaposi's sarcoma
KU Collection

    Kaposi's "sarcoma" (in AIDS or not) is a pseudo-tumorous infection caused by a recently-discovered herpes virus (KSHV / Herpes 8, 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.

      * 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.

      * 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).

    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 as etiologic agent (Medicine 70: 137, 1991) and/or myc activation. The brain lymphomas are always Epstein-Barr related (Lancet 338: 969, 1991).

    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.

      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.

      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.


    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.

    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.

      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).

        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-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.

      HIV-negative AIDS

      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, cryptosporidiosis, bad herpes simplex and/or zoster, hairy leukoplakia, tinea pedis ("athlete's foot"), tinea cruris ("crotch-rot"), others. Lymph nodes are usually enlarged.

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)
{05258} AIDS cachexia

      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.)

        "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).

      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

HIV lymphadenopathy

Yutaka Tsutsumi MD

    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

    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.

    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):

      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.


      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.


      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
      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%: ???


    How U.S. patients are catching AIDS now (CDC online 2004)

      42%: MSM's
      25%: IV drug abusers
      33%: heterosexual contacts, mostly of the above


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, herpes) also clearly increases risk (JAMA 260: 1429, 1988; Am. J. Pub. Health 81: 1576, 1991), and probably does for straight M's also.

      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, 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).

        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).


      A tisket, A tasket / A condom or a casket....
            -- Truck stop graffiti, 1991

      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.

Human aspects of AIDS (update NEJM 347: 357, 2002)

There are six things that clearly reduce the transmission of AIDS.

    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

* 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.)

    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.

    * 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:

  • testing on demand, with "post-test clubs" (regardless of result) where people support one another in maintaining healthy lifestyles;
  • treating other sexually-transmitted diseases (i.e., ulcers, urethritis);
  • an ad campaign urging people to wait until they'd met the right person, and then being faithful;
  • de-stigmatization and de-mystification
  • getting local communities to run their own programs
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.

* 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 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.

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
                Hosp. Pract. Feb. 15, 1994

* 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), 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.


    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

    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. Magic Johnson

    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).

      * 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.

      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.

    • The next generation of anti-HIV drugs will be the fusion inhibitors (entry inhibitors -- update Lancet 370: 81, 2007). Enfuvirtide, a synthetic peptide, is the first to be licensed for general use; it prevents the binding of gp41 and the cell membrane. Although expensive, it is of course very well-tolerated (Lancet 370: 39, 2007). See NEJM 348: 2175, 2003; molecular biology Proc. Nat. Acad. Sci. 100: 10598, 2003.
    • Other entry inhibitors will render you essentially CCR5-negative ("coreptor antagonists"; NEJM 348: 2228, 2003; Maraviroc, others) and/or block entry by other routes.
    • more non-nucleoside reverse-transcriptase inhibitors (a few years ago I urged folks to watch the drug TMC-125, and now it is coming available as etravirine as an investigational drug available for people whose treatment is failing)
    • Interleukin 2 to boost immunity towards the end: NEJM 332: 567, 1995. Lately there has been a resurgence of interest in this for both early and late HIV, as a way of bolstering CD4 cells (J. Inf. Dis. 185: S2, S115, 2002, others).
    • Interleukin 16, which has various effects on CD4, CXCR4, and CCR5 (J. Immuno. 165: 6356, 2000), represses HIV's promoter (J. Immuno. 158: 5, 1997), probably more.
    • The integrase inhibitors (Proc. Nat. Acad. Sci. 93: 6326, 1996) are no longer getting much attention. Maybe someday; there's one called S-1360 (Lancet 359: 767, 2002).
    • It sounds far-fetched, but it seems to help in animal models: a xenograft of pig thymus (from Harvard: J. Inf. Dis. 196: 900, 2007). Watch this one.

    * And of course there will be more grave disappointments.

      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).

      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).