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Progression from HIV to AIDSProgression is the term used to describe the process from HIV infection to AIDS to death. According to many this process is inexorable, even if there are years between HIV infection and the first AIDS-defining disease (or non-disease, for many diagnosed in the United States). There are many anomalies, however, when the scientific literature is examined.The quotes are categorized as:
Absence of Progression in LTNPs (Long Term Non-Progressors)Long Term Non-Progressors are HIV-positive people who have never taken AIDS drugs and who have remained in good health for years, in many cases for more than one or two decades. Why, given that these people exist, do doctors insist that HIV-positive people must take AIDS drugs?
“An HIV-positive man who didn’t tell his girlfriend he had the condition was sentenced to 12 years in prison Thursday…Neither [his girlfriend nor another sexual partner] contracted HIV despite their long-term relationship with Hunter, Jones said…Court documents said Hunter has hemophilia and got HIV through a blood transfusion when he was 7 years old. He attended the University of Arkansas, where he met at least one of the women.” Wood R. Man Gets Prison Term For Exposing Woman To HIV. The Morning News (Arkansas). 2008 May 1 http://www.nwaonline.net/articles/2008/05/01/news/050208fzhunter.txt “The NIH is conducting a research study to evaluate patients who have been able to control the progression of HIV for long periods without the use of antiretroviral therap…We will conduct genetic testing, blood collection and tissue sampling in the hope of better understanding how some rare individuals can suppress HIV without medications. [Although, without accurate statistics, it is not clear how this situation can be called rare]” Leukapheresis Procedures to Study HIV-Specific Immunity: 02-I-0086. NIAID. 2008 Mar [accessed] “In June 2006, a 77-year-old Japanese man with an acute asthma attack was admitted to our hospital in Yokohama, Japan. A pre-admission HIV screening test by enzyme immunoassay unexpectedly detected his HIV seropositivity…strong seroreactivity to HIV-2, but not to HIV-1 [and further tests confirmed this]…He had no history of engaging in high risk sexual contact and substance abuse in the past. Both his spouse (72 years old) and their son (34 years old) were HIV-negative. He, however, had a near-fetal[sic] motor accident in Senegal in June 1971…he received a large unit of blood from a number of volunteer Senegalian donors. He has never been transfused with blood products except on that occasion…After 8 days, he was discharged from hospital…His CD4 cell count was 827 cells/µL…He continues to be [a] long-term nonprogressor” Utsumi T et al. An HIV-2-infected Japanese man who was a long-term nonprogressor for 36 years. AIDS. 2007 Aug 20;21(13):1834-5. “The replicative potential of HIV-1 strains in a well characterized group of eight HIV controllers [people who have undetectable viral load for a long time without AIDS drugs] was investigated. Replication-competent viruses were detected in CD4 T-cell co-culture supernatants from all HIV controllers…Infection with HIV-1 variants with attenuated replicative capacity cannot be a general factor accounting for undetectable viraemia in HIV controllers.” Lamine A et al. Replication-competent HIV strains infect HIV controllers despite undetectable viremia (ANRS EP36 study). AIDS. 2007 May 11;21(8):1043-1045. “During a 5-month period, the outpatient records of all patients attending the Connaught Clinic in Harare, Zimbabwe, were screened; patients aged 8–19 years and their guardians were asked for written informed consent to participate…32 patients participated, with no refusals. The median age was 12 years, and 17 (53%) were male…Only 2 participants (6%) had both parents still alive; 12 (39%) had lost 1 parent, 17 (55%) had lost both parents, and data were missing for 1 patient…97% of the participants had below average height-for-age, and 100% were below average weight-for-age. The mean Z score ( SD) for height-for-age was -2.55, and the mean Z score ( SD) for weight-for-age was -2.32. 63% and 58% of participants had a Z score for height-for-age and for weight-for-age of less than 2, respectively. All participants had World Health Organization stage 3 or 4 HIV infection at presentation. The median CD4 cell count at diagnosis was 101 cells/µL. The majority of participants (91%) reported recurrent upper respiratory tract infections, chronic skin problems, and/or chronic diarrhea. Tuberculosis had been diagnosed on 1 occasion in 19 participants (59%) before the diagnosis of HIV infection was made; an additional 8 patients (25%) had been treated for tuberculosis at or after diagnosis of HIV infection [Note that the fraction of children acquiring HIV at birth and surviving 10 years is only believed to be about 15% or less and no adjustments were made for the economic and family circumstances of these children which were significantly worse than normal. The fact that all these children were sick is at least partly due to the fact that the study only investigated children who were ill, the number of healthy children who have been HIV+ since birth is unknown.]” Ferrand RA et al. HIV infection presenting in older children and adolescents: a case series from Harare, Zimbabwe. Clin Infect Dis. 2007 Mar 15;44(6):874-8. “there are people who progress very slowly to AIDS, in contrast to most of us who would progress at a certain rate, by year 7 or 8 you would be in trouble” Gallo RC. Testimony at appeal hearing of Andre Parenzee. Court of Criminal Appeal. 2007 Feb 12 http://garlan.rethinkingaids.info/Cases/Parenzee/Gallo.html “The DHCS [Danish HIV Cohort Study] is a prospective, nationwide, population based cohort study of all HIV-infected persons treated in Danish HIV clinics since 1 January 1995…We estimated median survival times and computed mortality rates from age 25 years separately for men and women and for the subgroup of HCV [Hepatitis C]-negative persons…All participants were observed from age 25 years: HIV-infected persons had a median survival of 19.9 years (17.5 years for men and 24.2 years for women), whereas persons from the general population had a median survival of 51.1 years (50.8 years for men and 54.8 years for women) (Table 3). During the late HAART period (2000 to 2005), median survival of HIV-infected patients had increased to 32.5 years (32.1 years for men and 32.3 years for women) overall, and to 38.9 years (37.8 years for men and 40.1 years for women) after persons with known HCV infection were excluded…the proportion of known causes of death that were related to HIV infection decreased from 76% in 1995 to 1996, to 57% in 1997 to 1999, and to 43% in 2000 to 2005 [Note that this study includes no information comparing actual medication usage, and did not even estimate how adherent to drugs patients who were being prescribed drugs were. The study also ignores other health issues (such as IV drug use) and the increasing health of people at time of HIV diagnosis over time.]” Lohse N et al. Survival of persons with and without HIV infection in Denmark, 1995-2005. Ann Intern Med. 2007 Jan 16;146(2):87-95. “It was in September that year [1989] that Joe Muriuki, a clerk with the Nairobi City Council, went for a HIV test because of some skin infection that refused to go and persistent night sweating that left him cold. But the news that awaited him was numbing. He was HIV positive. The worst was yet to come. Doctors predicted that it would be a matter of time before his wife, then three-weeks pregnant, also tested positive. In the light of those developments, they suggested that the Muriukis abort the foetus. Muriuki then started preparing for his death by packing his belongings to return to his rural home…“Those days, testing HIV positive was equated to a death sentence. It was a matter a months and...” Muriuki gestures helplessly. “You would be gone.”…Eighteen years on, Muriuki is convinced that one can live as healthy as others and he is a living testament of that resolve…Jane[his wife] tested negative but a prejudiced society found it hard to believe…An ever smiling Jane is the mother of three boys. Her last born, Eric Munyiri, the boy that doctors wanted terminated, was one of the top performers in the 2003 Kenya Certificate of Primary Education. “I had sought advice from a number of doctors who all felt that there was no need for me to give birth to a baby who would soon die,” Jane recalls.” But I rejected their advice and left everything to God.”…Jane, who was only 26 when Muriuki went public says, “Initially it was strange for me to be negative. I did not understand and thought maybe it was God’s will and therefore I decided to fully support my husband to overcome the social stigma or any unfairness he would encounter.”…After 18 years, Muriuki is not on ARVs, goes for periodic medical tests and generally keeps healthy by eating well. It’s called the spirit of life.” Kimani P, Wachira M. Aids patient lives on, 17 years later. The Nation (Kenya). 2007 Jan 6 “People with HIV have what is called HIV infection. Some [not “all”] of these people will develop AIDS as a result of their HIV infection.” What is HIV?. CDC. 2006 Oct 20 http://www.cdc.gov/hiv/resources/qa/qa1.htm “As many as one in 300 HIV patients never get sick and never suffer damage to their immune systems…the "elite" status is clearly defined by how much virus they have circulating in their blood [which means that there are almost certainly many people who are HIV-positive who never get sick but do have lowered CD4 cell counts, especially since we know that some people with lower than average CD4 cell counts are perfectly healthy]” Fox M. "Elite" HIV patients mystify doctors. Reuters. 2006 Aug 16 http://today.reuters.com/news/articlenews.aspx?type=healthNews&storyid=2006-08-16T215038Z_01_N16248997_RTRUKOC_0_US-AIDS-ELITE.xml&src=rss&rpc=22 “Of 2176 seroconverters, 145 (6.7%) spontaneously controlled viraemia [low viral load without antiretroviral therapy]” Madec Y et al. Spontaneous control of viral load and CD4 cell count progression among HIV-1 seroconverters. AIDS. 2005 Nov 18;19(17):2001-7. “It has been 16 years since Mr. Brothers learned he was H.I.V. positive. Since then, he has never taken AIDS drugs or had any illnesses associated with the disease…Since the epidemic began in 1981, Dr. Levy has been trying to understand why Mr. Brothers and others who are H.I.V. positive can remain medicine-free yet fit for decades, while the average person with H.I.V. progresses to AIDS within 10 years, if untreated…Some of Dr. Levy's subjects have been H.I.V. positive for 27 years, longer than there has been an epidemic.
The dates of infection were confirmed by the San Francisco Department of Public Health, which in 1978 began a hepatitis B study of 6,704 gay men, whose blood was preserved.” Pogash C. The inexplicable survivors of a widespread epidemic. NY Times. 2005 May 3 “At the Nyumbani children’s home, HIV-infected children rescued from the city’s slums have survived for more than 10 years without medication. Their natural immunity has intrigued scientists around the world. Researchers believe the orphans’ blood offers vital genetic clues that could lead to the holy grail of AIDS research: an effective vaccine” Scientists from Oxford University “stole the blood” of African orphans and brought it back to the UK to carry out “unlawful” research into AIDS. The Observer. 2004 May 31;7. “A cohort of 19 patients with evidence of nonprogressive HIV-1 infection [i.e. no AIDS-defining illnesses] was established in 1997 at our institution…in Madrid. All patients had serologically proven HIV-1 infection for at least 10 years, repeated CD4 cell counts >500 million cells/l, and no prior history of HIV-related symptoms, in the absence of any antiretroviral therapy. Most of these individuals had been exposed to HIV-1 before 1985 or 1987, when they first tested positive for HIV-1 antibodies. One subject was known to be HIV-1 seropositive since 1979, after testing retrospectively sera stored from that time. All of these individuals have been prospectively followed every 4–6 months since January 1997…All but one were former injecting drug users.” Rodes B et al. Differences in disease progression in a cohort of long-term non-progressors after more than 16 years of HIV-1 infection. AIDS. 2004 May 21;18(8):1109-16. “At Kenyatta National Hospital VCT centre, an estimate 10% to 15% of the couples who get tested turn out to be discordant [one HIV+, one HIV-]…’the infected partner is not getting opportunistic infections despite having the virus for a long time’, says Dr. Moses Otsyula, an HIV expert…Their CD4 counts are not declining…And they have very low viral loads” Okwemba A. Doctors ponder why some couples have mixed results. Horizon Magazine. 2003 Dec 18 “patients were categorized into two groups according to their current clinical status and CD4 cell count. 14 patients were categorized as long-term non-progressors (LTNPs), as defined by absence of symptoms without antiretroviral therapy and stable CD4+ T cell counts >500 cells/ml at a median 15 years of infection[!]. 3 additional LTNPs had progressed with a decline in their CD4+ T cell count to below 500 cells/ml shortly after their immunological evaluation and were therefore analysed as a separate subgroup. 12 patients were termed slow progressors (SPs), who had been infected for a median of 15 years but who showed evidence of disease progression (declining CD4+ T cell count below 500 cells/ml) [but apparently no illness!] at the time of study, but had not yet started antiviral therapy…There were no other significant demographic differences between LTNPs and SPs [apart from differences in CD4+ cell counts and 'viral load']” Papagno L et al. Comparison between HIV- and CMV-specific T cell responses in long-term HIV infected donors. Clin Exp Immunol. 2002 Dec;130(3):509-17. “The immune systems of non-progressors…manage to kill most of the virus before it can reproduce in great numbers. That’s true for [Steve] Newson, who tested positive in 1995.…researchers don’t think non-progressors will ever get AIDS. Scientists at the National Institute of Allergy and Infectious Diseases have been studying 17 people, including Newsom, 41, who fall into that category…’Here I am – on no drugs, no meds – doing better than anyone,’ Newson said, with a mix of sadness and astonishment. ‘Why?’ [maybe because you’re not taking any drugs?]” Shelton D. The power of natural resistance. Calgary Herald. 2002 Nov 9;OS4. “Our results identify a subset of HIV-infected individuals in whom control over disease progression is obtained in the absence of therapy. A deterioration of immune functions, CD4 cell reduction, or changes in viraemia [viral load] were not detected in these individuals during the study period. This fortunate condition is associated with: (i) higher CD8 cell counts; (ii) higher HIVspecific- and non-specific-stimulated proliferation as well as IL-2 and IFN-Gamma production; and (iii) a lower concentration of IL-7. Noticeably, this condition is also associated with low but detectable viraemia.” Clerici M et al. Early and late effects of highly active antiretroviral therapy: a 2 year follow-up of antiviral-treated and antiviral-naive chronically HIV-infected patients. AIDS. 2002 Sep 6;16(13):1767-73. “In recent years, increasing interest has been focused on the study of individuals who remain healthy, HIV-seronegative and with no evidence of infection despite well-documented sexual exposure to HIV (EU individuals). It has been suggested that in these individuals protection from HIV infection may result from either inheritance of a non-functional CCR5 coreceptor, low or defective virus inoculum or acquired sterilizing host immunity. Whereas a genetic basis for HIV resistance seems to account for a small proportion of EU cases, evidence that the immune system may control HIV-1 entry and/or replication has been reported in different cohorts of EU individuals: these individuals appear to respond to HIV-1 antigens with a wide panel of immune responses, ranging from HIV-specific mucosal antibodies to HIV-specific CD4+ T cells that produce high levels of CC chemokines or to HIV-specific CTL...Sixteen HIV-seropositive individuals and their uninfected heterosexual partners with a history of regular sexual exposure for more than 2 years were enrolled in the study. EU partners were repeatedly tested for HIV-1 infection (anti-HIV-1/2 antibodies, serum p24 antigen and plasma HIV-1 RNA), and genotyped for two protective CCR5 genetic polymorphisms...Only one individual, EU55, was found to be heterozygous for the CCR5-Ä32 allele, and none was found to carry the CCR5-m303 allele...Unstimulated CD8+ T [immune] cells from all the EU individuals, except one, induced a broad spectrum dose-dependent suppression of HIV-1 infection...[but] the capacity of CD8+ T cells to suppress HIV-1 was also documented in some HIV-seronegative unexposed controls” Furci L et al. Non-cytotoxic inhibition of HIV-1 infection by unstimulated CD8+ T lymphocytes from HIV-exposeduninfected individuals. AIDS. 2002;16(7):1003-8. “I, like most people living in developed countries, grew up with an unquestioning faith in modern medicine. While I continue to respect most of what my own doctor tells me, I am wary of his views regarding AIDS and HIV. On Feb. 6, 1986, shortly after my 27th birthday, my doctor told me I was HIV-positive. The fact that he had had me tested without my consent bothered me less than being told that, more than likely, I had only six months to live. There were then no medications for the condition. People were dying in great numbers. There seemed to be no hope…For more than 10 years I kept silent on the topic. I floated aimlessly in a deep depression…A year after I tested positive, the drug AZT became available for HIV patients. I was feeling fine, physically, and decided in my risky defiance not to begin any treatment until I started displaying symptoms of illness. However, I saw some dear friends who were also asymptomatic HIV-positives go on the drug and rapidly decline in health, suffering horrible deaths. Even to this day, through my 16 years of being HIV positive, I have never taken any AIDS drugs, and have never experienced any AIDS-related illness. I continue to enjoy good health. My T-cell count does fluctuate but I no longer panic, or think much about it.” Gilpin W. 'Slow progressor': AIDS 'cocktails' are saving lives, but some HIV-positives thrive without them. Macleans. 2002 May 20 “3 of the 8 recipients [of HIV infected blood between 1981 and 1984 in Sydney, Australia] are deceased [as of 2001]; 2 of the 3…died from causes unrelated to HIV-1 infection and a consensus has not been reached as to the cause of death of the third…The SBBC [Sydney Blood Bank Cohort] can be divided into two distinct groups, long-term non-progressors (LTNP) and long-term survivors (LTS). The LTNP comprise three recipients who are asymptomatic and satisfy a strict definition of non-progression: all have stable and normal CD4 T cell counts (>500 per cubic mm), viral loads are below detection and are therapy naïve [have never taken AIDS drugs]…the LTS [also 3] all have significantly declining CD4 T cell counts and detectable but low VL” Birch MR et al. An examination of signs of disease progression in survivors of the Sydney Blood Bank Cohort (SBBC). J Clin Virol. 2001 Oct;22(3):263-70. “A large number of people from within the general population, that is, those not part of the “high-risk group” enjoy good health despite testing “HIV positive” a decade ago. In Mumbai, the “AIDS capital of India,” counseling groups such as Salvation Army and CASA (Counseling and Allied Services), who attend to HIV-positive people from this segment of the population say there is strong evidence to show that the damage caused to the immune system can be reversed. “This happens when people change their habits of substance abuse, eat nutritious food, involve themselves in community service, practice discipline and hygiene, receive regular counseling, family and social support. Such persons emerge stronger and healthy,” says Arun Meitram, a counselor at the Salvation Army clinic. Incidentally, Salvation Army counselors recall only 15 deaths have occurred among the 900 patients they have been following over the past decade. In most cases the cause of death is related to malnutrition or TB. Says Nagesh Shirgoppikar, a medical consultant to Salvation Army, “Our experience in treating ‘HIV positive’ persons over the past decade shows that all the components of comprehensive psychological, emotional, physical and conventional medical treatment are very important. If a person is treated wholly, he is fine. Our patients have remained asymptomatic for up to ten years, and enjoy perfect health without anti-retroviral drugs.”” Chinai R. AIDS cocktail. Times of India. 2001 May 29 “By 10 years after seroconversion 7.3% of the haemophilic men had died without AIDS and 38.2% had developed AIDS. These figures were 20.2% and 30.5% for injecting drug users, and 8% and 55% for homosexual men.” Prins M et al. Pre-AIDS mortality and its association with HIV disease progression in haemophilic men, injecting drug users and homosexual men. AIDS. 2000;14:1829-37. “We have been following a 78-year-old man who, as a result of a test performed before cataract surgery in 1985, was found to be seropositive for HIV-1…He has never had any symptoms or signs of HIV infection, and repeated clinical examinations and laboratory tests performed since 1985 have revealed no opportunistic infections or abnormalities other than HIV-1 seropositivity and glucose-6-phosphate dehydrogenase deficiency…No evidence of CCR5 mutations [that are believed to confer immunity] was found” Sulis E, Lusso P, Contu L. Prolonged Asymptomatic HIV-1 Infection. N Engl J Med. 2000 Apr 20;342(16):1221-2. “LTNP [long-term non-progressor (to AIDS)] status was defined as asymptomatic HIV-1 infection for at least 8 years with stable CD4+ cell counts and no antiretroviral therapy...A wide range of plasma viral loads was observed among the LTNPs...Among the 47 LTNPs with plasma viral load higher than 800 copies/ml, 30 had a viral load higher than 10,000 copies/ml and 3 had a viral load higher than 500,000 copies/ml despite fulfilling the inclusion criteria…Patients in the control [comparison] group had asymptomatic HIV infection for 8 years with CD4 cell counts between 300 and 400 cells per cubic millimeter], a CD4 decrease of at least 25% in the last 3 years, and no antiretroviral therapy…Due to increasing frequency of therapy among subjects with CD4 < 500 cells, the enrollment of asymptomatic control subjects with no anti-HIV therapy was more difficult [indicating that healthy people are pressured to go on therapy due to their CD4 cell counts in the absence of any illness]” Candotti D et al. Status of long-term asymptomatic HIV-1 infection correlates with viral load but not with virus replication properties and cell tropism. J Med Virol. 1999 Jul;58(3):256-63. “6 HIV-infected individuals were identified in whom the CD4 : CD8 ratio remained normal throughout follow-up (4.0-11.25 years). They all maintained levels of CD4+ cells above 500 million/l and had never received antiretroviral therapy. Because HIV-specific cytotoxic [cell killing] T lymphocytes (CTL) have been implicated in control of HIV during the asymptomatic phase of disease, we screened these individuals for the presence of HIV-specific CTL activity…None of the six immunologically normal HIV-infected subjects exhibited direct HIV-specific CTL activity in their freshly isolated PBMC compared with 16 (47%) out of 34 HIV disease progressors…Plasma HIV viraemia ['viral load'] in all six INHI subjects was below the level of detection by branched DNA assay (< 500 copies/ml). Virus could not be isolated from four of these individuals despite multiple attempts to do so by PBMC coculture assays…Despite the absence of cells activated for killing HIV-infected targets in the circulation of these individuals, they appeared able to control their HIV infection by maintaining normal levels of CD4 and CD8 cells and low viral load.” Bernard NF et al. HIV-specific cytotoxic T-lymphocyte activity in immunologically normal HIV-infected persons. AIDS. 1998 Nov 12;12(16):2125-39. “A third category of infected individuals consists of the long-term survivors, also called long-term nonprogressors, who have remained healthy with normal CD4+ cell numbers for at least 10 years. Some groups have predicted that up to 13% of homosexual/bisexual men infected at a young age will remain asymptomatic for more than 20 years. The usual percentage of these long-term survivors is 8 to 10% of the total number of infected people. These asymptomatic people can also be found among infected hemophiliacs, intravenous drug users, heterosexual contacts, and newborn children…About 10 to 25% of infected newborn children develop AIDS within the first 2 years of life, whereas the rest can have a slower progression to disease, with some remaining healthy for several years…another group of infected individuals has an unusual clinical presentation. They remain free of illness and AIDS symptoms for more than 3 years after their CD4+ cell counts have dropped below 200 cells/microliter…The reason for this lack of progression in the absence of treatment has not been explained” Levy JA. HIV and the pathogenesis of AIDS [2nd ed.]. ASM Press. 1998 “Recently, a subset of HIV-1–infected persons who appear to successfully control virus replication in the absence of antiretroviral therapy has been identified. Despite infections of up to 18 or more years, these individuals maintain normal CD41 T cell counts, low to undetectable viral loads, and have no evidence of HIV-1–related disease manifestations…Initial studies were performed in an HIV-1–infected hemophiliac with 18 years of documented seropositivity, a normal CD4+ T cell count, and a viral load of <400 RNA molecules per milliliter of plasma, who had never been treated with antiretroviral agents…we next examined the association between plasma HIV-1 RNA viral load and lymphocyte proliferative responses in a cohort of individuals with a wide range of viral loads. Ten HIV- 1–infected individuals with varying clinical histories and viral loads who had never been treated with antiretroviral therapy were evaluated” Rosenberg ES et al. Vigorous HIV-1–Specific CD4+ T Cell Responses Associated with Control of Viremia. Science. 1997 Nov 21;278:1447-50. “[In this study of 78 HIV-positive people with high CD4 cell counts and no symptoms] there were no differences in viral load with regard to time of HIV-1 infection [i.e. amount of virus does not grow over time]…10 patients fulfilled the criteria for LTNP [Long Term Non-Progressors]. 7 of these 10 patients had viral loads above 10,000 RNA copies/ml and 2 above 30,000 RNA copies/ml. The level of viral load of LTNP was not statistically different compared with the other 68 patients.” García F et al. Viral load in asymptomatic patients with CD4+ lymphocyte counts above 500 million/l. AIDS. 1997;11:53-7. “during the past three years, it has become evident that: (1) a small percentage of HIV-seropositive individuals maintain a stable CD4+ T-cell count and do not exhibit signs of AIDS, despite having been infected with HIV for more than ten years… and (2) there are individuals who have been exposed to HIV (some on multiple occasions) but do not seroconvert or show signs of HIV infection…our laboratory has studied gay men who have unprotected sex, intravenous drug users, newborns of HIV+ mothers and HCWs [Health Care Workers]…63% of seronegative gay men, 76% of intravenous drug users, 35% of newborns of HIV+ mothers and 75% of HCWs exposed to HIV+ blood responded to two or more peptides [presumed HIV antigens]…Negative controls for these studies included: presumed unexposed adult individuals (controls for the gay men and drug users, respectively) who showed 2.5% and 3.1% positive responses; newborns of HIV- mothers…who showed 0% positive responses; and HCWs accidentally exposed to seronegative blood…who showed 24% positive responses [lending weight to the theory, not considered by these authors, that ‘HIV’ antibodies might actually be due to autoimmune or alloimmune reactions]…it is extremely important [to the financial health of the AIDS industry?] that the seronegative status of HIV-exposed individuals is not presumed to reflect naturally acquired protection.” Shearer G, Clerici M. Protective immunity against HIV infection: has nature done the experiment for us?. Immunology Today. 1996;17(1):21-4. “LTNPs [Long-term non-progressors] were defined as having documented HIV-1 infection for >7 years, CD4 cell counts of >600 cells/cubic mm, and no symptoms related to HIV-1 infection. With the exception of [two of nineteen] patients, no patients had ever received antiretroviral therapy.” Montefiori DC et al. Neutralizing and infection-enhancing antibody responses to HIV type-1 in long-term nonprogressors. J Infect Dis. 1996;173:60-67. “The median duration of infection at the time of evaluation [of these people with ‘stable nonprogression HIV type 1 infection’] was 14 years (range 11-15), and none of these individuals had been treated with antiretroviral agents.” Harrer T et al. Strong cytotoxic T cell and weak neutralizing antibody responses in a subset of person with stable nonprogressing HIV type 1 infection. AIDS Res Hum Retro. 1996 May 1;12(7):585-92. “Data from the first 14 study visits were used to define a group of men who had maintained a stable number of T-helper lymphocytes (CD4+ lymphocytes) over a long period of time…All men who were seropositive at entry [into the study] and had CD4+ lymphocyte data available from the third and fourth visits were eligible for this analysis…It is important that the individuals had not taken the antiretroviral drug zidovudine…A second subgroup of the 293 individuals with long-term follow-up and no use of zidovudine was chosen as one comparison control group [but this group had some CD4 cell decline]” Muñoz A, Kirby AJ et al. Long-term survivors with HIV-1 infection; incubation period and longitudinal patterns of CD4+ lymphocytes. J Acquir Immune Defic Syndr. 1995 Apr 15;8(5):496-505. “In a small percentage of persons infected with human immunodeficiency virus type 1 (HIV-1), there is no progression of disease and CD4+ T-cell counts remain stable for many years...We studied 15 subjects with long-term nonprogressive HIV infection and 18 subjects with progressive HIV disease. Nonprogressive infection was defined as seven or more years of documented HIV infection, with more than 600 CD4+ T cells per cubic millimeter, no antiretroviral therapy, and no HIV-related disease.” Pantaleo G et al. Studies in subjects with long-term nonprogressive Human Immunodeficiency Virus Infection. N Engl J Med. 1995 Jan 26;332(4):209-16. “We studied 10 seropositive subjects who remained asymptomatic with normal and stable CD4+ lymphocyte counts despite 12 to 15 years of HIV-1 infection. Plasma cultures were uniformly negative for infectious virus. However, particle-associated HIV-1 RNA was detected in four subjects with a sensitive branched-DNA signal-amplification assay, whereas in five others the levels of HIV-1 RNA were too low to detect. Infectious HIV-1 was detected in peripheral-blood mononuclear cells (PBMC) of three subjects by standard limiting-dilution cultures, and infectious virus was recovered from another subject with use of a CD8-depleted culture. The other six subjects had no detectable infectious virus in their PBMC. A quantitative polymerase-chain-reaction assay revealed that all subjects had detectable but low titers of viral DNA in PBMC. Overall, the viral burden in the plasma and PBMC of long-term survivors was orders of magnitude lower than that typically found in subjects with progressive disease.” Cao Y, Qin L, Zhang L et al. Virologic and immunologic characterization of long-term survivors of HIV-type 1 infection. N Engl J Med. 1995 Jan 26;332(4):201-208. “There are individuals with long-term HIV infection who appear clinically and immunologically healthy 10-15 years after HIV seroconversion, with stable CD4+ counts. Lack of exposure to STD or recreational drugs does not appear to explain the delayed course of disease progression in HLP.” Buchbinder S et al. Long-term HIV-1 infection without immunologic progression. AIDS. 1994 Aug;8(8):1123. “Eight LTNP (i.e. infected for more than 7 years, CD4+ cell slope > or = 0, no antiretroviral therapy) were studied. Viral burden and viral replication were significantly lower, (at least 1 log), in both mononuclear cells isolated from PB [peripheral blood] and LN [lymph nodes] of LTNP compared to the levels observed in PB and LN of 20 normal progressors…[however,] Virus isolated from PB and LN of LTNP is infectious and replication competent.” Fauci AS. Studies on HIV infected individuals who are long term non-progressors. Multicenter AIDS Cohort Study (MACS). Int Conf AIDS. 1994 Aug 7-12;10(19-049B). http://gateway.nlm.nih.gov/MeetingAbstracts/ma?f=102208461.html “Father Angelo d’Agostino is puzzled. He sits at the heart of Africa’s alleged AIDS epidemic with a hospital full of HIV-positive children who, health experts say, are condemned to die. Except that they are very much alive. As a result, d’Agostini, in common with growing numbers of scientists and doctors around the world, is beginning to question whether HIV really is the killer it has been made out to be. He, like them, suspects that many “AIDS” cases are really old diseases given a new name and that people who test HIV-positive are not, as most have been led to believe, the victims of a new, inevitably lethal disease. As founder of the Nyumbani hospice for abandoned and orphaned HIV-positive children in Nairobi, Kenya, he had expected to see much disease and death. But his so-called “AIDS babies” are confounding all predictions. A year has passed since the home opened and only one of his first 45 children has been lost an ailing six-week-old infant who had to return to hospital almost immediately and died two weeks later. The rest, who are aged up to six years, are thriving and Nyumbani, which means “at home”, teems with life and laughter. Yet elsewhere in Kenya and across sub-Saharan Africa, according to the World Health Organisation (WHO), tens of thousands of children are dying because of HIV, usually in their first year.” Hodgkinson N. Babies give lie to African AIDS. The Sunday Times. 1993 Aug 29 “LTNP: Individuals who have been living with HIV for at least 7 to 12 years (different authors use different time spans) and have stable CD4+ T cell counts of 600 or more cells per cubic millimeter of blood, no HIV-related diseases, and no previous antiretroviral therapy. Data suggest that this phenomenon is associated with the maintenance of the integrity of the lymphoid tissues and with less virus trapping in the lymph nodes than is seen in other individuals living with HIV.” HIV/AIDS Treatment Access Network Glossary. http://glossary.hivatis.org/index.asp
Progression to AIDS and CD4 countsIt was originally believed that HIV caused AIDS by killing CD4 immune cells. But this was proven false. Now most researchers talk about Ôimmune activationÕ, except that nobody can explain how this is connected to the death of CD4 cells. So here we have it, almost 30 years after AIDS was declared to be a new syndrome Ð still no explanation for the death of CD4 cells.
“A model of CD4 T-cell depletion based entirely on direct virus infection and killing of these cells was put forward in the mid 1990s [5,6]. This so-called ‘tap-and-drain’ model proposed that progression to AIDS in HIV-infected individuals resulted from a failure of the immune system’s homeostatic response to keep up with a high rate of loss of CD4 T cells…However, this model and its later versions were challenged on theoretical and experimental grounds as they did not appear to grasp the complexity of T-cell dynamics in response to ongoing viral replication and painted a simplistic picture of AIDS pathogenesis. The idea that chronic immune activation plays a major role in AIDS pathogenesis was first put forward by Ascher and Sheppard [in 1988] and, in parallel – but from a rather different perspective – by Grossman and colleagues in the late 1980s/early 1990s…[then follows a long explanation for the evidence that the immune system of many people diagnosed with AIDS shows signs of over-activation]…it should be noted from the outset that although many lines of evidence indicate that chronic immune activation is a key determinant of immunodeficiency in HIV-infected individuals, the exact mechanisms by which this phenomenon induces CD4 T-cell depletion and disease progression are still largely unknown, and in fact may vary in different classes of patients. The possibilities discussed below are largely hypothetical…[then follows a long discussion of unproven possible ways to connect the observation that immune systems are activated to the depletion of CD4 cells]…a large set of data suggest that targeting the HIV-associated immune activation may represent a promising therapeutic strategy to be considered, in addition to ART, in the clinical management of HIV infection. [the bottom line, this theory, proven or not, could prove to be very profitable]” Sodora DL, Silvestri G. Immune activation and AIDS pathogenesis. AIDS. 2008 Feb 19;22(4):439-46. “the most strongly prognostic factor from the start of HAART [to AIDS or death] was the CD4 cell count at baseline. Patients with IDU [IV Drug Use] as the likely mode of transmission, or with an AIDS diagnosis at baseline were also at a substantially increased risk of progression.” Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies. AIDS. 2007 May 31;21(9):1185-97. “A runaway cycle in which elevated CD4+ T cell activation and proliferation drive HIV production and vice versa cannot explain the pace of depletion during chronic HIV infection.” Yates A et al. Understanding the slow depletion of memory CD4+ T cells in HIV infection. PLoS Medicine. 2007 May;4(5):e177. “Over the next 5 years with 2304 women-years of follow-up, 299 (46.1%) of the women [in a group of poor, American women with a significant history of heroin or cocaine use] progressed to a CDC defined AIDS diagnosis. Only 20 women developed either a confirmed or probable opportunistic condition as their AIDS-defining even…An additional 279 women developed AIDS, based on a drop in their CD4 lymphocyte count to <200 cells/cubic-mm. Thus, 93.3% of the AIDS diagnosis in the cohort were based on CD4 criteria.” Mayer KH et al. Clinical and immunologic progression in HIV-infected US women before and after the introduction of highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2003 Aug 15;33(5):614-24.
AIDS 'Progression' Among ChildrenStories vary widely about the progression of AIDS among children. Some authors claim that it is virtually universally fatal by age five, others say that the death rate is very high at first and then slows down, still others claim that if the other risk factors of the children are adjusted for (malnutrition, parental drug use etc.) that there might not be much additional risk left over.
“[In African children WITHOUT HIV being diagnosed] 86.1% of surveyed households were in the poorest Kenya socioeconomic quintile…among children aged 6–35 months, 21.5% had experienced an acute respiratory infection and 9.1% had experienced diarrhea in the preceding 24 hours, 28.0% had chronic malnutrition, 66.2% had anemia, and 19.8% had a positive malaria smear.” Baseline data from the Nyando integrated child health and education project – Kenya, 2007. MMWR. 2007 Oct 22 http://www.cdc.gov/mmwr/PDF/wk/mm56e1022.pdf “Uninfected infants born to immunosuppressed HIV+ mothers appear to be at increased risk of mortality. This increase is not explained by the risks associated with separation because of maternal death or hospitalization nor does it result from lower birth weight. Advanced maternal HIV disease may be associated with as yet unidentified nutritional or immunologic deficiencies that may adversely affect intrauterine and postnatal development even of uninfected infants.” Kuhn L et al. Not Infected but still Affected: Prognosis of Uninfected Infants Born to HIV+ Mothers in Zambia. Retrovirus Conference. 2005 Feb;Abstract 805. “We used Cox proportional hazards models to calculate rate ratios (relative risk) of neonatal (0-28 days), postnatal (29-365 days) and infant (0-365 days) mortality in relation to low birth weight and HIV transmission…HIV transmission was not significantly associated with neonatal mortality…[after adjustments for other variables] low birth weight was associated with a 2-fold increased risk of infant mortality…Compared with infants not known to be HIV-positive at 1 year of age, babies diagnosed of infection within 21 days after birth were 10.42 times more likely to die during the postneonatal period or 6.21 times more likely to die during the first year of life…low birth weight , not HIV infection was associated with an increased risk of neonatal mortality…low birth weight was associated with an increased risk of mortality only in the uninfected infants.” Wei R et al. Association between low birth weight and infant mortality in children born to human immunodeficiency virus 1-infected mothers in Tanzania. Pediatr Infect Dis J. 2004 Jun;23(6):530-5. “50% of vertically infected children in Africa are assumed to survive to 2 years old and 40% to 5 years old, with subsequent low mortality for an undetermined period.” Gisselquist D, Potterat JJ, Brody S. HIV transmission during paediatric health care in sub-Saharan Africa--risks and evidence. S Afr Med J. 2004 Feb;94(2):109-16. “[At age 10 the risk of death within the next year for CD4 at 10%, 20%, 30% and 40% was, respectively, 2.1%, 0.3%, 0.2% and 0.2%]” HIV Paediatric Prognostic Markers Collaborative Study Group. Short-term risk of disease progression in HIV-1-infected children receiving no antiretroviral therapy or zidovudine monotherapy: a meta-analysis. Lancet. 2003 Nov 15;362(9396). http://www.thelancet.com/journal/vol362/iss9396/full/llan.362.9396.original_research.27745.1 “Women who were [HIV-]seropositive were significantly more likely than women who were seronegative to be delivered of low-birth-weight infants and IUGR [Intra-Uterine Growth Restriction] infants; to experience perinatal deaths, and to be delivered of infants with 5-minute Apgar scores of <7…[after re-analysis to exclude confounding factors] the increased risk of low birth weight persisted. Independent risk factors that are associated with low birth weight include alcohol use, no prenatal care, hypertension, <100% ideal body weight, presence of STDs [sexually transmitted diseases], and fetal distress. [note that the use of illicit drugs was not considered, a bit surprising for a study in a US inner-city hospital]” Ellis J et al. Human immunodeficiency virus infection is a risk factor for adverse perinatal outcome. Am J Obstet Gynecol. 2002 May;186(5 Pt 1):903-6. “34 HIV-infected children aged 10 years or older were currently being observed…most children, including most of those with AIDS, were well and without symptoms for most of the time (in nearly 3/4 of clinic visits), as is the case for all the infected children in the ECS [European Collaborative Study] as a whole, although HAART has only become widely used in the last 3 years” Thorne C et al. Older Children and Adolescents Surviving With Vertically Acquired HIV Infection. J Acquir Immune Defic Syndr. 2002 Apr 1;29(4):396-401. “Survival estimates of the progression to CDC class C disease [AIDS] or death indicate that 6% (2-11%) of infected children in this group would have progressed by the age of 1 year, 17% (10-24%) by the age of 5 years, and 22% (13-31%) by 10 years of age [note that it is normally expected that 50% of HIV-infected people will progress to AIDS in 10 years]...children who had received combination therapy were estimated to have a non-[statistically-]significantly increased rate of clinical progression” European Collaborative Study. Level and pattern of HIV-1-RNA viral load over age: differences between girls and boys?. AIDS. 2002 Jan 4;16(1):97-104. “In this prospective cohort study of children born to HIV-1-infected black women, we found that children with vertically transmitted infection showed early onset of stunting and were generally malnourished. However, children with rapidly progressive disease had both wasting and stunting, with the differences in weight and length and length being present from birth. [Indicating that AIDS in Africa has more to do with malnourishment than anything else]…Studies from Rwanda and Uganda [also] found that children with vertically acquired HIV-1 infection were frequently undernourished and were stunted but not wasted. Similar reuslts have been reported from New York, where infected children [a large number infants of drug addicted mothers] were [frequently] found to have early stunting…It is not clear why HIV-infected children have growth failure [Duh, maybe their mothers are malnourished or (in North America) drug users?]…Infected children with low weight and length-for weight were more likely to have had persistent diarrhoea, chronic fever and pneumonia [Take the word 'Infected' from the beginning of the sentence and you will see that it is totally irrelevant]” Bobat R et al. Growth in early childhood in a cohort of children born to HIV-1-infected women from Durban, South Africa. Ann Trop Paediatr. 2001 Sep;21(3):203-10. “By age 6 years only 3% of children do not progress to stage A [minor symptoms]…Progression to category C [AIDS - opportunistic infection, encephalopathy or a recurrent serious bacterial infection (no other symptoms reported)]…[reached] a total of 36% by age 6 years…An estimated 26% of infected children die of HIV infection before 6 years of age…Of the 106 children in category C, 40 (38%) had no signs of immune suppression (CDC classification) at the time of illness, whereas 27 (25%) had a moderate and 39 (37%) a severe immune deficit…74% of children will survive beyond age 6…the CDC classification reflects the childrens’ lifetime experience and not their current health. 23 of the 31 children in categories B or C reached these categories in the first 2 years of life, and most had no further category B- or C-defining condition for several years subsequently. Only one of the 39 children [observed at age 6] had shown no signs of immune deficiency. 13 (33%) had CD4 cell counts suggesting moderate suppression, and 25 (64%) had severe suppression. Of the latter, only 4 (15%) had been diagnosed with a category C condition. 21 children with severe [immune] suppression had not progressed to severe clinical disease, although they had been at risk for 4-64 months…In our analysis, based on information collected from birth, the large majority of infected children survive beyond the age of 6 years, and one third of the children alive at 6 years were asymptomatic or have only mild symptoms and were not severely immunocompromised. Most of these children had experienced transient group A or B illnesses and a moderate immune deficiency at an early age. Had they not been part of a prospective study, a diagnosis of HIV infection may not have been made.
The clinical classification in the 1994 CDC definitions is simple and discriminatory because most deaths occurred in patients in clinical stage C. The immunological classification did not related closely to clinical progression. [The CDC classification] reflects lifetime experience rather than current health status, and it does not allow children to be reclassified to a less serious category as their symptoms disappear.” Blanche S et al. Morbidity and mortality in European children vertically infected by HIV-1. The French Pediatric HIV Infection Study Group and European Collaborative Study. J Acquir Immune Defic Syndr. 1997 Apr 15;14(5):442-50. “All HIV-1-infected children will ultimately die [no reference given]” Nagelkerke NJ et al. The duration of breastfeeding by HIV-1 infected mothers in developing countries: balancing benefits and risks. J Acquir Immune Defic Syndr. 1995 Feb;8(2):176-181. “Although after the age of 1 year immunologic abnormalities (e.g. low CD4 cell counts) became increasingly common, the proportion of infected children with significant HIV-related symptoms or signs declined…not all of the [HIV-infected children] were symptomatic continuously; many improved during the second and third years of life…Indeed, of the 15 children with AIDS who were still alive when last seen, only 4 met the definition of symptomatic…Results from [this] cohort suggest that about one quarter of infected children develop AIDS in the first year of life and about 40% by age 4 years…It is now apparent that untreated infected children can survive for a considerable length of time with only minor HIV-related signs” European Collaborative Study. Natural history of vertically acquired human immunodeficiency virus. Pediatrics. 1994 Dec;94(6Pt1):815-9. “44% of the infants whose mothers had Class IV disease [AIDS] died before the age of 18 months, as compared with 9 percent of the infants whose mothers had class II [no symptoms] or III [swollen glands] disease [this paper also reports that treatment with AZT was more common in mothers with AIDS]” Blanche S et al. Relation of the course of HIV infection in children to the severity of the disease in their mothers at delivery. N Engl J Med. 1994 Feb 3;330(5):308-12. “To study long-term survival we selected infected children who were regularly followe-up and aged at least 5 years at last examination (defined as long-term survivors (LTS)). The findings were compared with those of children who died of HIV-1-related disease during infancy or in early childhood (age <5 years) (defined as short-term survivors (STS)). 1063 seroreverted (SR) children served as controls of T-cell subset numbers by age…71% of children were still alive at 5 years, and 68% at 6.5 years…[Table 1 shows that STS had more than 3 times the rate of anemia and hepatitis than LTS]” Italian Register for HIV INfection in Children. Features of children perinatally infected with HIV-1 surviving longer than 5 years. Lancet. 1994 Jan 22;343(8891):191-5. “[Table 3 shows that the death rate in babies of HIV-negative mothers was 4.6%, that of HIV+ babies of HIV+ mothers was 50%. Surprisingly, the death rate among indeterminate babies was also 50% and among HIV- babies of HIV+ mothers was only 0.7%]” Lepage P et al. Mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) and its determinants: a cohort study in Kigali, Rwanda. Am J Epidemiol. 1993 Mar 15;137(6):589-99. http://aje.oxfordjournals.org.ezproxy.lib.ucalgary.ca/cgi/reprint/137/6/589.pdf “Through 1989, 5.3% of 95 [HIV-]infected hemophiliacs aged 5 to 13 years developed AIDS, compared with 20.3% of 364 aged >=25 years.” Fletcher MA et al. Effect of age on human immunodeficiency virus type 1-induced changes in lymphocyte populations among persons with congenital clotting disorders. Transfusion Safety Study Group. Blood. 1992 Aug 1;80(3):831-40. “Postnatal mortality in infants of HIV-infected mothers followed up from birth was increased 15-fold over the general population with a very high incidence (2 in 100) of sudden infant death syndrome apparently unrelated to HIV infection [but]...Intravenous drug use (IVDU) was reported...for 68% of mothers; 46% of them were reported to have used drugs during pregnancy...Neonatal signs of drug withdrawal were seen in 19% of the infants [could this be why their babies were sicker?]” Kind C et al. Epidemiology of vertically transmitted HIV-1 infection in Switzerland: results of a nationwide prospective study. Eur J Pediatr. 1992;151:442-8. “In Kigali, perinatally HIV-1-infected children surviving beyond 5 years of age often present with moderate signs and symptoms [no symptoms in 2 of 16 children studied], principally pulomonary involvement, chronic parotitis, and persistent generalized lymphadeopathy. Short status is the major clinical manifestation in these patients.” Lepage P et al. Clinical and endocrinologic manifestations in perinatally human immunodeficiency virus type 1--Infected children aged 5 years or older. AJDC. 1991 Nov;145(11):1248-51. “By 12 months, 26% have AIDS and 17% died of HIV-related disease. Subsequently the disease progresses more slowly and most children remain stable or even improve during the second year” European Collaborative Study. Children born to women with HIV-1 infection: natural history and risk of transmission. Lancet. 1991 Feb 2;337(8736):253-60.
Co-Factors in Progression to AIDSThe HIV/AIDS theory claims that it alone is the cause of disease. Yet it is quite clear that, for many people, there are other risk factors, such as IV drug use. This is a slippery slope, if co-factors are necessary for progression from HIV to AIDS, is HIV even necessary for AIDS?
“Of 1551 HIV-1-infected individuals screened for helminth [parasitic worm] infection, 299 were helminth infected. 234 adults were enrolled and underwent randomization and 208 individuals were included in intent-to-treat analyses. Mean CD4 cell count was 557 cells/microl and mean plasma viral load was 4.75 log10 copies/ml at enrollment. Albendazole therapy resulted in significantly higher CD4 cell counts among individuals with Ascaris lumbricoides infection after 12 weeks of follow-up and a trend for 0.54 log10 lower HIV-1 RNA levels. These effects were not seen with treatment of other species of soil-transmitted helminths. [implying that at least one species of helminth reduces CD4 counts, and that part of what is known as ‘viral load’ may be due to these parasites]” Walson JL et al. Albendazole treatment of HIV-1 and helminth co-infection: a randomized, double-blind, placebo-controlled trial. AIDS. 2008 Aug 20;22(13):1601-9. “Severe anaemia in childhood is a life threatening condition and an important cause of hospital admission in many developing countries. In Malawi in 1990, one in eight inpatient paediatric deaths were related to anaemia. Impaired mental and motor development of young children is associated with iron deficiency anaemia” le Cessie S et al. Changes in haemoglobin levels in infants in Malawi: effect of low birth wieght and fetal anaemia. Arch Dis Child Fetal Neonatal Ed. 2002 May;86(3):F182-7. “positive serostatus was associated with increased support from health professionals, the break-up of a marriage and being neglected or disowned by their family. Serodiscordant couples [one HIV+, one HIV-] with an HIV-positive woman were most likely to report the break up of a marriage...Disclosure was associated with strengthening of a sexual relationship [i.e. in HIV-positive men] except for HIV-seropositive women” Grinstead OA et al. Positive and negative life events after counselling and testing: the voluntary HIV-1 counselling and testing efficacy study. AIDS. 2001 May 25;15(8):1019-23. “Anemia is a common manifestation of infection by HIV [and of retroviral drugs, such as AZT], occurring in approximately 30% of patients with asymptomatic HIV and in as many as 75% to 80% of those with clinical AIDS. In a retrospective evaluation of medical records of 32,867 HIV-infected persons followed in nine cities in the United States, the 1-year incidence of anemia, defined as a hemoglobin level <10 g/dl or a physician’s diagnosis of anemia, was approximately 37% for patients with a clinical AIDS-defining condition; 12% for those with immunologic AIDS, defined as a CD4 count <200; and 3% for persons without either of these conditions…Several factors were shown to be independently associated with anemia among HIV-infected women in our cohort…CD4 count, HIV RNA in plasma, history of AIDS, use of ZDV [AZT], African American race, and low MCV [Mean Corpuscular Volume] of red blood cells…Use of ZDV either currently or in the past 6 months was associated with anemia…A total of 41.5% of those with a history of ZDV in the past 6 months and 27.7% of those without such history were anemic at baseline” Levine AM et al. Prevalence and correlates of anemia in a large cohort of HIV-infected women: Women's Interagency HIV Study. J Acquir Immune Defic Syndr. 2001 Jan 1;26(1):28-35. “Nutritional deficiencies are widespread among HIV-1-seropositive male and female drug abusers (injecting drug users, or IDUs), among men who have sex with men (MSM), and among children, although the prevalence of nutritional alterations varies among the groups. Low levels of vitamin A, vitamin B12, zinc, and Selenium are common and have been demonstrated to be associated with disease progression and HIV-1 related mortality, independent of CD4 count <200 cells/mm3 at baseline and CD4 count over time. When all nutrient factors that are associated with survival are considered together, only Selenium deficiency is a significant predictor of mortality. The profound effect of Selenium on disease progression may reflect Selenium's action in antioxidant defense systems, as well as gene regulation.” Baum MK. Role of micronutrients in HIV-infected intravenous drug users. J Acquir Immune Defic Syndr. 2000 Oct 1;25 Suppl 1:S49-52. “Over the course of the study, 12 [of 24] children died of HIV-related causes…only CD4 cell count below 200 and low levels of plasma selenium were significantly and independently related to mortality. Among the children who died, those with low selenium levels died at a younger age” Campa A et al. Mortality risk in selenium-deficient HIV-positive children. J Acquir Immune Defic Syndr. 1999 Apr 15;20(5):508-13. “Nutritional deficiencies may contribute to immune dysregulation, and have been shown to be sensitive markers of HIV-1 disease progression…Immune and nutritional measurements were obtained in a subsample of 125 subjects from a larger cohort of drug users being followed for HIV-1 infection and cofactors of disease progression. Nutritional deficiencies, particularly vitamins A, E, and zinc, were widespread with up to 86% of the drug users exhibiting at least one nutritional alteration. Although immune parameters (CD4 count, CD8 count, beta2-microglobulin) were similar in the HIV-1-infected men and women, women had significantly poorer overall nutritional status, as measured by plasma proteins, which are considered to be sensitive markers of malnutrition.” Baum MK et al. HIV-1 infection in women is associated with severe nutritional deficiencies. J Acquir Immune Defic Syndr Hum Retrovirol. 1997 Dec 1;16(4):272-8. “plasma levels of vitamins A, E, B6, and B12 and minerals selenium and zinc were considered in relation to relative risk for HIV-related mortality. Immune parameters and nutrients known to affect immune function were evaluated at 6-month intervals in 125 HIV-1-seropositive drug-using men and women in Miami, FL, over 3.5 years. A total of 21 of the HIV-1-infected participants died of HIV-related causes during the 3.5-year longitudinal study. Subclinical malnutrition, vitamin B12 deficiency, zinc deficiency, and selenium deficiency over time, but not zidovudine treatment, were shown to each be associated with HIV-1-related mortality independent of CD4 cell counts <200/mm3 at baseline, and CD4 counts over time.” Baum MK et al. High risk of HIV-related mortality is associated with selenium deficiency. J Acquir Immune Defic Syndr Hum Retrovirol. 1997 Aug 15;15(5):370-4.
The Influence of Genetics on Progression to AIDSOccasionally there is great excitement with the announcement that a gene prevents progression to AIDS. But usually the effect found is quite minor and, quite often, future research doesn't support the initial hypothesis.
“Association of CTLA4 genotypes with clinical and virological outcomes following HIV-1 infection appeared to vary with time and among the cohorts.” Shao W et al. Cohort- and time-specific associations of CTLA4 genotypes with HIV-1 disease progression. AIDS. 2006 Aug 1;20(12):1583-1590. “Five LTNP (33%) were found to be secretor-positive (se+/+ [homozygous], se+/- [heterozygous]) and 10 (67%) se-/-. Of the 19 individuals with normal HIV-1 progression 15 (79 %) were found to be secretor positive and four (21%) were non-secretors [homozygous negative]. No frequency differences were found in the Delta32 CCR5 allele among the groups studied…Strong association (P < 0.001) was observed between the nonsense mutation 428G-->A in the FUT2 gene and a slow disease progression of HIV-1 infection. [but, given the small numbers, caution should be applied to this conclusion]” Kindberg E et al. A nonsense mutation (428G-->A) in the fucosyltransferase FUT2 gene affects the progression of HIV-1 infection. AIDS. 2006 Mar 21;20(5):685-689. “The DC-SIGNR homozygous 7/7 repeat was found to be associated with an increased risk of HIV-1 infection (17.5% in high-risk HIV-1-seronegative individuals vs. 28.5% in HIV-1-seropositive individuals), whereas the DC-SIGNR heterozygous 7/5 repeat tended to be correlated with resistance to HIV-1 infection (35.5% in high-risk HIV-1-seronegative individuals vs. 27.6% in HIV-1-seropositive individuals; P=.0291) [but note that neither of these are stunningly strong associations]]” Liu H et al. Repeat-Region Polymorphisms in the Gene for the Dendritic Cell-Specific Intercellular Adhesion Molecule-3-Grabbing Nonintegrin-Related Molecule: Effects on HIV-1 Susceptibility. J Infect Dis. 2006 Mar 1;193(5):698-702. “CEM15 (or APOBEC3G) has recently been identified as an inhibitor of human immunodeficiency virus type 1 (HIV-1) replication in vitro. To evaluate the impact of its genetic variations on the progression of acquired immunodeficiency syndrome (AIDS), we have performed an extensive genetic analysis of CEM15. We have sequenced CEM15 in a cohort of 327 HIV-1-seropositive patients with extreme disease progression phenotypes--either slow progression or rapid progression--and in 446 healthy control subjects, all of white descent. We have identified 29 polymorphisms with allele frequencies >1%, 14 of which were newly characterized. There were no significant associations between the polymorphisms or haplotypes of CEM15 and a disease progression phenotype in our cohort” Do H et al. Exhaustive Genotyping of the CEM15 (APOBEC3G) Gene and Absence of Association with AIDS Progression in a French Cohort. J Infect Dis. 2005 Jan 15;191(2):159-63. “A cohort of 19 LTNP [Long-Term Non-Progressors] was established in 1997. Plasma viraemia and CD4 cell counts were measured two to three times each year until 2003. Analyses of nef and vpr viral genes, CCR5 genotypes, co-receptor tropism, viral replication capacity, and immunological parameters were performed…None of the patients was homozygous for the delta-32 CCR5 genotype, which was found in heterozygosis in three.” Rodes B et al. Differences in disease progression in a cohort of long-term non-progressors after more than 16 years of HIV-1 infection. AIDS. 2004 May 21;18(8):1109-16. “Only one individual, EU55, was found to be heterozygous for the CCR5-Ä32 allele, and none was found to carry the CCR5-m303 allele” Furci L et al. Non-cytotoxic inhibition of HIV-1 infection by unstimulated CD8+ T lymphocytes from HIV-exposeduninfected individuals. AIDS. 2002;16(7):1003-8. “Among hemophiliacs from the Multicenter Hemophilia Cohort Study who remained HIV-1 seronegative despite a high (94%) risk for acquisition of HIV-1 infection, only 7/43 were homozygous for the protective CCR5 Delta32 polymorphism. Among the remainder, neither CCR5 density nor beta-chemokine production, nor in vitro susceptibility to infection with the HIV-1 isolate JR-FL could distinguish HRSN hemophiliacs from healthy controls.” Salkowitz JR et al. Characterization of High-Risk HIV-1 Seronegative Hemophiliacs. Clin Immunol. 2001 Feb;98(2):200-211. “It has been hypothesized that protection against human immunodeficiency virus (HIV)-1 infection may result from either acquired host immunity, inheritance of a dysfunctional CCR5 HIV-1 coreceptor, or a low or attenuated virus inoculum. Thirty-seven HIV-1-uninfected persons engaging in repeated high-risk sexual activity with an HIV-1-infected partner were prospectively studied to determine the contribution of these factors in protecting against HIV-1 transmission. More than one-third (13/36) demonstrated HIV-1-specific cytotoxicity, and this activity significantly correlated with the wild type CCR5 genotype (P=.03). Only 1 subject (3%) demonstrated the homozygous CCR5 32-bp deletion (Delta32/Delta32). Median plasma HIV-1 RNA levels from 18 HIV-1-infected sex partners were not statistically different from those of matched infected control patients. These results indicate that inheritance of the Delta32 CCR5 mutation does not account for the majority of persistently HIV-1-resistant cases” Goh WC et al. Protection against human immunodeficiency virus type 1 infection in persons with repeated exposure: evidence for T cell immunity in the absence of inherited CCR5 coreceptor defects. J Infect Dis. 1999 Mar;179(3):548-57. “Env peptide-stimulated PBMCs of ESNs produced more IL-2 and less IL-10 compared with those of HIV-infected individuals; no differences were observed in chemokine production or in CCR5 expression.” Mazzoli S et al. HIV-specific mucosal and cellular immunity in HIV-seronegative partners of HIV-seropositive individuals. Nat Med. 1997 Nov;3(11):1250-7.
Progression Among HemophiliacsThe AIDS industry believes that hemophiliacs have been getting sick because of HIV, but others argue that it was the introduction of the first AIDS drug, AZT, in 1987 that started killing them.
“In 1983, he heard hemophiliacs were developing AIDS, then a mysterious disease that usually claimed its victims in two or three years…A year later, he was infected…Surprisingly, he stayed relatively healthy for a decade. He thought he had escaped a death sentence, but in 1997 his appetite began to wane. By 2000, he had advanced [but unspecified here] symptoms of AIDS…he was too stubborn, and too suspicious about doctors, to take the new antiretroviral drugs that were by then extending the lives of many AIDS patients…He gave in to Alice’s pleas and started to take the new drugs after she convinced him they were not poison. The drugs worked. Mackie said they at first caused a dangerous reaction that left him “out of his head” but eventually gave him more energy and confidence. Despite being weak from AIDS and Hepatitis C [huh? A sentence ago he had more energy!], which he found out he had in 2000 [the same year he started taking AIDS drugs], Mackie insisted on giving evidence to the Archer committee last year [2007]…Alice read most of his statement, and he spoke quietly when he spoke at all, but he did raise his voice at one point…Andrew March, a hemophiliac in London who became HIV positive when he was nine [1983] after exposure to tainted blood plasma products…[he] is now 34 and generally free of AIDS symptoms.” Katz G. Victim of tainted blood scandal speaks. AP. 2008 Aug 23 http://news.aol.com/health/article/victim-of-tainted-blood-scandal-speaks/145617?icid=100214839x1208353898x1200469601 “Of the 94 [HIV-positive hemophiliac] patients, 31 (33%) developed AIDS. 42 patients died, 13 of them without developing AIDS. Of the 29 patients who died after developing AIDS, death was due to AIDS-related causes in 24, and hepatic failure in one, while in the remaining 4 patients the cause of death was unknown. The Kaplan-Meier estimate for the rate of progression to AIDS after 16 years of follow-up was 38% [indicating that the average time from HIV seroconversion to AIDS is considerably more than the 10 years normally estimated]…In the multivariate analysis, only age at seroconversion [which is a factor of the lifetime exposure to clotting factor] and the type of hemophilia were independently associated with progression to AIDS…patients with hemophilia B [who use clotting Factor IX] have a 16 times higher risk [of AIDS] than hemophilia A patients [a much more common form of hemophilia which requires Factor VIII]” Lorenzo JI et al. Progression to acquired immunodeficiency syndrome in 94 human immunodeficiency virus-positive hemophiliacs with long-term follow-up. Haematologica. 2001 Mar;86(3):291-6. “[In a study of British hemophiliacs with a median seroconversion date of late 1982] The annual death rate in patients with severe haemophilia remained steady at 8 per 1,000 during 1977-84, but then rose progressively to 38 in 1991-92. This increase was confined to patient who tested seropositive for HIV and among whom the death rate increased steeply from 1985, reaching 81 in 1991-92. Among moderate/mild patients [who were HIV-positive]…the death rate again rose steeply during 1985-92…Treatment, by prophylaxis against Pneumocystis carinii pneumonia or with zidovudine [AZT], has been widespread for HIV-infected haemophiliacs since about 1989 [actually, since 1987 when AZT was first approved for treatment of AIDS], However, the steady increase in the excess death rate from 1985 to 1992 suggests that in this population the increasing impact of HIV-associated mortality has not been halted by these treatments [but no consideration of whether the treatments might be causing some or all of the excess death rate]. This study includes deaths only until 1992, and so does not permit examination of data following widespread use in the UK of high purity factor concentrate…During 1985-92, 403 deaths occurred in seropositive patients and for 235 of these the certified cause was AIDS. For the remaining 168 deaths…there were significant excesses for many causes indicative of AIDS [but also associated with the therapy used], including infections, non-Hodgkin’s lymphoma and pneumonia, and also significant excesses for causes associated with haemophilia.” Darby SC et al. Mortality before and after HIV infection in the complete UK population of haemophiliacs. Nature. 1995 Sep 7;377(6544):79-82. “The cumulative incidence of AIDS over an 8-year period [among Italian hemophiliacs] was 17.0%…the cumulative incidence of AIDS by age at seroconversion estimated over 8 years…[was] 32.5% for the >=35 group, 16.4% for the <=12 group, and 15.1% for the 13-34 year-old group…The cumulative incidence of AIDS over the 8-year period was significantly greater among severe factor IX recipients (23.3%) than among severe factor VIII recipients (14.2%)…only 5/53 patients on low mean dosages of replacement therapy (due to a mild/moderate congenital coagulation disorder) have developed AIDS,yielding a 10.4% cumulative incidence of AIDS detectable over an 8-year period; the cumulative incidence for patients on high dosages of plasma-concentrates…in the same period was 15.2%…The cumulative incidence of AIDS over the 8-year period was estimated 18.8% for factor VIII recipients (severe A hemophiliacs) that used on average <=20,000 IU and 10.9% …[for those] that used on average >20,000 IU. Estimated cumulative incidences of AIDS over the 8-year period were respectively 23.6% for factor IX recipients (severe B hemophiliacs) on low (<=7,500 IU) dosages, and 17.2% for severe B hemophiliacs on high (>7,500 IU) dosages…Patients included in this study used a wide variety of plasma-derived concentrates…Other cut-off values for concentrate consumption (such as 30 000, 45 000, and 60 000) consistently yielded a trend towards slower progression to AIDS in recipients of low than of high amounts of factor VIII, yet in no case differences at 5% level of probability were observed…this trend is not apparent for factor IX recipients” Schinaia N et al. Clinical factors associated with progression to AIDS in the Italian cohort of HIV-positive hemophiliacs. G.I.C.C. Gruppo Italiano Coagulopatie Congenite. Thromb Haemost. 1994 Jul;72(1):33-8. “Analysis by geographic regions showed significant increases in mortality [among hemophiliacs] in each region from 1979-1981 to 1987-1989 [when AZT first became available]…Comparisons of the age at death…demonstrate the marked shift…to lower ages in recent years” Chorba TL et al. Changes in longevity and causes of death among persons with hemophilia A. Am J Hematol. 1994 Feb;45(2):112-21. “We designed a multicentre, prospective, randomised, controlled study of symptom-free HIV-infected patients with haemophilia A who were assigned to receive either an intermediate-purity [Factor VIII blood clotting factor] or monoclonal-antibody-purified [‘high purity’] product…35 completed the 3 year study, 20 in the monoclonal arm and 15 in the intermediate-purity arm [many in this arm leaving to start on high purity Factor VIII]. Among those completing the study, there were no differences between the two groups in the occurrence of AIDS-defining diagnoses (1 in each group). There were, however, striking and significant differences in terms of changes in absolute CD4 counts. The group receiving monoclonal-antibody-purified concentrates had essentially stable counts while a significant drop was observed in the group receiving intermediate-purity F[actor] VIII. These differences were independent of the use of antiretroviral therapy.” Seremetis SV et al. Three-year randomised study of high-purity or intermediate-purity factor VIII concentrates in symptom-free HIV-seropositive haemophiliacs: effects on immune status. Lancet. 1993 Sep 18;342(8873):700-3. “36 subjects treated with high-purity [Factor VIII blood clotting] concentrate for 6 months or more had a smaller decline in CD4 than 72 matched controls on intermediate-purity concentrate. In a more complex analysis with 226 subjects, CD4 counts declined 3% less per 6 months with high-purity material than with intermediate product (p = 0.04).” Hilgartner MW et al. Purity of factor VIII concentrates and serial CD4 counts. The Transfusion Safety Study Group. Lancet. 1993 May 29;341(8857):1373-4. “A wide spectrum of qualitative and quantitative immunological abnormalities are seen in patients infected with human immunodeficiency virus…evidence of similar immunological disturbances has been observed, albeit to a lesser degree, in anti-HIV-negative hemophiliacs…Skin tests using a new antigen, dinitrochlorobenzene (DNCB), have realed that anti-HIV-negative hemophiliacs are to a large extent unable to develop delayed hypersensitivity responses. The response was inversely correlated with the annual amount of [blood clotting] factor VIII infused. Many hemophiliacs demonstrate skin-test anergy to recall antigens as well, and poor reactivity correlates more strongly with annual consumption of factor concentrates than with HIV status…[immune suppression may be because] On exposure to plasma protein from 0.5 million donors over a period of 10 years, even small interindividual variations in the structure of substances such as fibrinogen, fibronectin, Factor VII and Ig imply a significant repeated challenge with alloantigens” Schulman S. Effects of factor VIII concentrates on the immune system in hemophilic patients. Ann Hematol. 1991 Sep;63(3):145-51. “Unlike the case in previous studies in both homosexuals and hemophiliacs, we did not observe a precipitous drop in CD-4+ count prior to the development of AIDS. The CD-4+ count of patients who ultimately developed AIDS fell at a rate of 50 cells/6 months compared to 175.8 cells/6 months witnessed by Eyster and colleagues...a dramatic drop in CD-4+ count was not a hallmark of the impending development of AIDS” Becherer PR et al. Human immunodeficiency virus-1 disease progression in hemophiliacs. Am J Hematol. 1990;34:204-9.
How Long from HIV to AIDS?In the 1980s it was often claimed that HIV infection led to AIDS very quickly, but as time went on the asymptomatic period was stretched out until now the consensus is that it is about 10 years, both in countries where HIV testing and AIDS drugs are common, and in poorer countries where they are not.
“[According to Table 2 on page 11, forty percent of people who received a 'diagnosis of HIV infection' (i.e. positive HIV test) in 2004 in 33 states and dependencies with name-based reporting received an AIDS diagnosis less than one year later. Compare this to the Muñoz study of 1997 that showed an average of 10 years from HIV infection to the first signs of AIDS. Why are people 'progressing' to AIDS so much faster now with all the new drugs available? Is it because of the new drugs?]” HIV/AIDS surveillance report, 2005. CDC. 2006;17. http://www.cdc.gov/hiv/topics/surveillance/resources/reports/2005report/pdf/2005SurveillanceReport.pdf “Johns Hopkins researcher Stephen Gange said records of a large group of gay men studied in the late 1980s showed that seven out of 10,000 cases developed AIDS within six months of infection.” Brown D. Drug-resistant AIDS case remains a puzzle. Washington Post. 2005 Feb 25 “The median time from seroconversion to AIDS was 9.4 years [This is very similar to times to AIDS seen in Western countries] [Note: The authors did not calculate time from HIV seroconversion to AIDS for those under 40 separately. This would presumably be significantly longer than 9.4 years]” Morgan D et al. HIV-1 infection in rural Africa: is there a difference in median time to AIDS and survival compared with that in industrialized countries?. AIDS. 2002 Mar 8;16:597-603. “Clinical manifestations of AIDS include severe, unexplained immune deficiency which generally [not always?] involves a depletion of helper T lymphocytes. These may be accompanied by malignancies and infections. The mortality rate for patients with AIDS is high. A less severe form of AIDS also exists, in which there may be lymphadenopathy and depressed helper T cell counts, there is not, however, the devastating illness characteristic of full-blown AIDS. There are many individuals, who are classified as having early AIDS (pre-AIDS), who exhibit these signs. It is not now possible to predict who among them will develop the more serious symptoms.” Chang NT et al. Cloning and Expression of HTLV-III DNA. US Patent Office. 1999 Dec 14;6,001,977. “The risk for developing AIDS among individuals in the ISS [Italian Seroconversion Study] cohort was less than 50% by 10 years after HIV seroconversion.” Rezza G. Determinants of progression to AIDS in HIV-infected individuals: an update from the Italian Seroconversion Study. J Acquir Immune Defic Syndr. 1998;17 Suppl 1:S13-6. “we estimate that between 21 and 40% (95% confidence interval) [of healthy, HIV+ people not using antiretroviral drugs] will be free from clinical AIDS 12 years from seroconversion and between 10 and 17%…20 years from seroconversion.” Muñoz A et al. The incubation period of AIDS. AIDS. 1997;11 Suppl A:S69-76. “In adults, the average time between infection and development of AIDS is 10 to 11 years” Mellors JW et al. Prognosis in HIV infection predicted by the quantity of virus in plasma. Science. 1996 May 24;272(5265):1167-70. “The ranges of the estimates of the median of the incubation period of AIDS [time from HIV infection to first AIDS-defining disease] have been found to be 8.3-10.7 years in homo-bisexual men, 10.2-11.6 years in injecting drug users (IDU), and 12.6-16.5 years in hemophiliacs” Muñoz A, Kirby AJ et al. Long-term survivors with HIV-1 infection; incubation period and longitudinal patterns of CD4+ lymphocytes. J Acquir Immune Defic Syndr. 1995 Apr 15;8(5):496-505. “Symptomatic seroconverters were significantly more likely to develop Centers for Disease Control and Prevention stage IV disease…A glandular-fever-like illness associated with seroconversion to HIV-1 [in a minority of people] predicts accelerated progression to AIDS and other HIV related diseases” Lindback S et al. Does symptomatic primary HIV- infection accelerate progression to CDC stage IV disease, CD4 count below 200 million/liter, AIDS, and death from AIDS?. BMJ. 1994 Dec 10;309:1535. “We analysed information on [hemophiliac, HIV-infected] patients up to 1 January 1993…Since 1989 patients have also been given monoclonal high purity factor VIII concentrate instead of intermediate purity product when the CD4 count fell below 200/ml. After 1991 all patients were switched to this product, which may slow the fall in CD4 count in HIV infected men with haemophilia…Over all age groups…the predicted percentage remaining free of AIDS [defined as CD4 counts <50/ml] for 20 years was 25%” Phillips AN et al. Use of CD4 lymphocyte count to predict long-term survival free of AIDS after HIV infection. BMJ. 1994 Jul 30;309(6950):309-13. “the incidence of HIV infection rose sharply in the early 1980s but fell rapidly after 1983-1984...[Table 3 shows that cumulative AIDS incidence after 7 years was 39.8% among homosexual men, 27.3% among adults with hemophilia and 19.7% among children with hemophilia]” Biggar, RJ et al. AIDS incubation in 1891 HIV-seroconverters from different exposure groups. AIDS. 1990;4(11):1059-66. “It appears that in the absence of treatment, most infected persons will progress to AIDS, with a median time to progression of 7-10 years from infection [but Table 1 shows only one study that has followed HIV+ people for 10 years since seroconversion with a rate of progression to AIDS of only 48%, and this group was one of the fastest progressing groups that they studied]” Moss AR, Bacchetti P. Natural history of HIV infection. AIDS. 1989 Feb;3(2):55-61. “The maximum likelihood estimate of the mean incubation period [from HIV infection to AIDS] is 7.8 years, which is similar to the estimate of the mean based on TA[transfusion associated]-AIDS for adults…since AIDS has such a long mean incubation period…which is longer than the follow-up time for most of our cases, infected men who have not yet developed AIDS cannot be physically distinguished from infected men who will never develop AIDS” Lui KJ et al. A model-based estimate of the mean incubation period for AIDS in homosexual men. Science. 1988 Jun 3;240(4857):1333-5. “[in transfusion recipients] the mean incubation period [from HIV infection to AIDS was] 1.97 years for children (0-4 years old at infection), 8.23 years for adults (5-59 years old), 5.5 years for elderly patients (60 years and older)” Medley GF et al. Incubation period of AIDS in patients infected via blood transfusion. Nature. 1987 Aug 20-26;328(6132):719-21. “On the basis of six pairs of patients, a mean latency period of 10.5 months is estimated between sexual contact and symptom onset.” Auerbach DM et al. Cluster of cases of the acquired immune deficiency syndrome. Patients linked by sexual contact. Am J Med. 1984 Mar;76(3):487-92. “the California cluster investigation and other epidemiologic findings suggest a 'latent period' of several months to 2 years between exposure and recognizable clinical illness” Current Trends Prevention of acquired immune deficiency syndrome (AIDS): Report of inter-agency recommendations. MMWR. 1983;32:101-3. | ||||||||||||||||||||||||||||||||||||
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