Haemostasis 1992;22:281-292

Centro de Hemofilia, Servicio de Hematología y Hcmoterapia, Hospital La Paz, Madrid, Spain

AIDS and Hemophilia: Experience in the La Paz Hemophilia Center

KeyWords

Abstract

Hemophilia AIDS Prognostic markers Antiviral therapy

435 hemophiliacs are usually being attended in the La Paz hemophilia Center (Madrid, Spain). 257 (59%) of these pa­ tients have been infected by the human immunodeficiency virus (HIV-1) because of human plasma derivate substitution therapy. The infection has been more frequent among the severely affected patients and among the most treated pa­ tients. 82% of the infected patients are between 14 and 40 years old. By December 1991, 95 (37%) of 257 seropositive patients have developed full-blown AIDS. The most frequent opportunistic infection they had suffered was esophageal can­ didiasis. Looking for an evolution marker, we can point that the patients older than 35 years with CD4 levels below 200/mm3 had the worst prognosis. There was no difference in the evolution among the patients aged below 17 and those aged between 17 and 35 years. The amount of concentrate used between 1980 and 1984 did not hold any relation to the evolution. 49 patients (51%) of the 95 suffering from AIDS had died by December 1991. The evolution to the death was unrelated to the patient age, CD4 lymphocyte levels, and amount of substitution therapy. In our opinion, the most valu­ able marker could be the kind of opportunistic infection or tumor the patient suffers from. Finally. Retrovir has demon­ strated to be useful in increasing the survival rate of the patients, but after 36 months of treatment, only 33% of those AIDS patients who began taking it remained alive. Retrovir was also used in asymptomatic patients, and during an aver­ age period of time of 15 months, a lesser bone marrow toxicity and a stabilization in CD4 lymphocyte levels could be ob­ served, but this was unable to modify the disease progression in those patients who presented circulating p24 antigen.

Dr. M. Magallón Martinez Hospital La Paz, Centro de Hemofilia Paseo de la Castellana. 261 E-28046 Madrid (Spain)

© 1992 S. Karger AG. Basel 0301-0147/92/ 0225-0281$2.75/0

Downloaded by: Nagoya University 133.6.82.173 - 1/15/2019 12:47:48 AM

M. Magallón Martinez F. Ortega J. Pinilla

Incidence of Seropositivity

We have designated as ‘usual attending pa­ tients’ those who come to our center at least once a year. According to these characteristics and up to 1986 (the year during which the serological diagnostic tests were made in all patients), we gathered 364 (84%) patients suf­ fering from hemophilia A and 71 (16%) pa­ tients suffering from hemophilia B. According to the levels of circulating coagulation factor, the disease was classified as severe (n = 210, 48%, factor level < 1%; moderate (n = 106, 25%, factor level 1-5%), and mild (n = 119, 27%, factor level > 5%).

282

Table 1. Incidence of HIV-1 seropositivity among the hemophiliacs in the La Paz Center

Hemophilia A Hemophilia B

Positive

Negative

n

%

n

%

226 31

62 41

138 40

38 59

Total

364 71

Table 2. Classification of the patients according to the amount of substitutive therapy received during the period 1980-1984

Group

Treatment, U/kg/year

I II III IV V VI

never treated only treated before 1980 1-500 501-1,000 1,001-3,000 > 3,000

Serological HIV screening revealed that 257 (59%) patients were HIV positive and 179 (41%) HIV negative. Since mid-1983, all of the La Paz Hemo­ philia Center’s hemophiliacs received only heat-treated antihemophilic concentrates for their substitutive therapy. Heat treatment has proved to be an efficient procedure capable of inactivating HIV-1 [1], Therefore, we can suppose that all data on which we are going to comment could be transferred to 1984, seeing that from this year onwards no more infec­ tions occurred and that all infected patients were seroconverted. According to the hemo­ philia type, the incidence of seropositive pa­ tients was different (table 1). The patients were classified into six groups, according to the average amount of coagulant units received per kilogram body weight and

Magallon Martinez/Ortega/Pinilla

AIDS and Hemophilia

Downloaded by: Nagoya University 133.6.82.173 - 1/15/2019 12:47:48 AM

HIV infection, acquired through human plasma derived coagulation factor concen­ trates, has devastated the hemophiliac popu­ lation, provoking a high incidence of immu­ nological troubles and infectious illnesses or tumors, all of which carry a bad prognosis. This situation has produced a stressing and fearful atmosphere among the patients, their relatives, and the medical staff. Nothing like this had ocurred until the HIV appearance; therefore, the immunological alterations sec­ ondary to the repeated injections of foreign proteins carried by these concentrates cannot be as serious as those produced by the virus. In the La Paz Hemophilia Center, the first hemophiliac patients suffering from AIDS was diagnosed in 1983. The retrospective clinical studies carried out suggest tha the ear­ liest infections happened in 1979. The situation created by HIV infection among the hemophiliacs attending the La Paz Hemophilia Center will be commented from a clinical point of view. We will divide the study into four different sections: (1) incidence of seropositivity; (2) evolution from seropositivity to AIDS; (3) deaths due to AIDS; and (4) effects of the therapeutic approaches.

Evolution from Seropositivity to AIDS

During the last few years, the number of seropositive hemophiliacs who have been AIDS diagnosed yearly has followed a pattern very similar to the number of total AIDS cases diagnosed in Spain, as can be seen from fig­ ure 4.

Table 3. HIV-1 seropositivity related to the thera­

peutic group Group

I II III IV V VI Unknown

Positive

Negative

n

%

n

%

0 2 43 46 90 72 4

0 15 33 69 87 92 18

20 11 89 21 13 6 18

100 85 67 31 13 8 82

Total

20 13 132 67 103 78 22

Table 4. HIV-1 seropositivity related to the age of

the patients Age, years

< 10 11-20 21-30 31-40 41-50 >50

Positive

Negative

n

%

n

%

12 80 86 48 20 11

25 62 73 65 48 42

35 48 32 26 22 15

75 32 27 35 52 58

Total

47 128 98 74 42 26

Table 5. HIV-1 seropositivity related to the sever­ ity of the coagulopathy

Severe Moderate Mild

Positive

Negative

n

%

n

%

167 61 29

79 57 29

43 45 90

21 43 71

Total

210 106 119

283

Downloaded by: Nagoya University 133.6.82.173 - 1/15/2019 12:47:48 AM

per year, from 1980 to 1984 (table 2). Table 3 shows the patient groups according to treat­ ment and their situation related to HIV seropositivity. The percentage of seropositive pa­ tients increased with regard to the increase of coagulant units used. The incidence of seropositivity was 92% in the group of the most intensively treated patients. It is also interest­ ing to note the low frequency of seropositivity in the patients treated before 1980. Some differences can also be observed in the incidence of seropositivity when the pa­ tients were classified according to age (ta­ ble 4). The most affected group ( 11 -40 years of age) consisted of the patients who were more intensively treated because of a more active life. The group with a noticeably smaller number of séropositives was that con­ sisting of patients under the age of 10 years because most of them had exclusively re­ ceived heat-treated concentrates since the first hemorrhagic episode. The incidence of infections related to the severity of hemophilia is shown in table 5. Again, we can observe that the patients with the most severe coagulopathies, and, there­ fore, the most frequently treated, were those who presented the highest incidence of sero­ positivity. This increase is due to the higher virus exposition rate because of the high fre­ quency of treatments and, moreover, to the possibility of numerous reinfections. Fig­ ures 1-3 show the same results, combining age and severity of the coagulapathy.

Fig. 1. Percentage of seropositivity to HIV-1 among severe he­ mophiliacs related to age. 80% of these patients were seropositive.

Fig. 3. Percentage of seropositivity to HIV-1 among mild hemo­ philiacs related to age. 22% of these patients were seropositive.

284

Magallon Martinez/Ortega/Pinilla

AIDS and Hemophilia

Downloaded by: Nagoya University 133.6.82.173 - 1/15/2019 12:47:48 AM

Fig. 2. Percentage of seropositivity to HIV-1 among moderate hemophiliacs related to age. 59% of these patients were seropositive.

Fig. 4. Total number of AIDS patients diagnosed per year in Spain related to the AIDS hemo­ philiacs diagnosed in the La Paz Hemophilia Center.

Age The classification according to the age of the AIDS patients in 1986 revealed the results shown in table 7. In our experience, a prereq­ uisite for a worst prognosis is being older than 35 years, while the probability to develop blown AIDS is similar under this age. These results differ from those found in the litera­ ture [6-9], but we must bear in mind the fact that the starting age for our study was when the patient had seroconverted and not when he has been infected (in our cases the greatest difference was 7 years).

%

Fig. 5. Yearly cumulative incidence of AIDS among seropositive hemophiliac patients in the La Paz Hemophilia Center.

CD4 Lymphocyte Levels The CD4 lymphocyte levels at the time of diagnosis in AIDS patients and seropositive patients are shown in table 8. In 82% of the cases the CD4 levels were below 200/mm3. This seems to be a bad prognostic marker, but when we consider the CD4 level distribution among the seropositive patients (32% of whom have levels > 200/mm3), we must ac­ cept this as not being a very exact marker.

285

Downloaded by: Nagoya University 133.6.82.173 - 1/15/2019 12:47:48 AM

95 AIDS cases have been diagnosed in the La Paz Hemophilia Center as far as Decem­ ber 1991. The cumulative incidence was 37% among the HIV-seropositive patients (fig. 5). The diseases and symptoms which led to the diagnosis of AIDS arc shown in table 6 ac­ cording to the criteria of the Center for Dis­ ease Control. With respect to some causes that would explain the different ways in the development of infection [2-11], we have studied (1) the age of the patients; (2) the CD4 lymphocyte levels at the time of diagnosis, and (3) the previous amount of antihemo­ philic concentrate received.

Deaths due to AIDS

By December 1991, 49 (51%) of the 95 AIDS patients were dead (table 10). When we consider the death rates among AIDS patients in our country, we can observe that they are very similar to the other patients infected through blood transfusions or hemoderivatives and higher than the percentage of all diagnosed patients. Just as we did in the pre­ vious sections, we are going to comment on the possible implications of three variables in the progression to death among the AIDS patients: (1) age and deaths; (2) CD4 lympho­ cyte levels in relation to death rate, and (3) amount of antihemophilic concentrate re­ ceived and deaths. Age and Deaths The ages referred to are those of 1986. According to this concept, the age distribu­ tion was as shown in table 11. We can see a higher percentage of deaths in the patients over 35 years of age when their seropositivity was demonstrated, but when the patients have developed AIDS, the progression to death is not related to age.

286

Table 6. Diseases and symptoms leading to the diagnosis of AIDS among the seropositive patients in the La Paz Hemophilia Center

Number of cases Oesophageal candidiasis Pneumocystis carinii pneumonia Constitutional disease Cerebral toxoplasmosis Recurrent infections (in children) Extrapulmonary tuberculosis HIV encephalopathy Cytomegalovirus Intestinal cryptosporidiosis Lymphoma Meningeal cryptococcosis Interstitial lymphoid pneumonitis Kaposi’s sarcoma

34 27 6 5 5 5 4 2 2 2 1 1 1

Table 7. Development of AIDS related to age

Age, years

Number of cases

AIDS patients n

%

77 127 53

24 44 27

31 35 50

< 17 18-35 > 35

Table 8. CD4 lymphocyte levels in AIDS patients and in HIV-1-seropositive patients

CD4/mm3

< 100 100-200 201-500 > 500

Magallön Martinez/Ortega/Pinilla

AIDS patients n

%

47 21 13 2

57 25 16 2

AIDS and Hemophilia

Seropositive patients, % (1991) 10 22 37 16

Downloaded by: Nagoya University 133.6.82.173 - 1/15/2019 12:47:48 AM

Previous Amount o f Antihemophiliac Concentrate In table 9 the AIDS patients are arranged according to their therapeutic regimen. We tried to find out whether in a determined group a worst prognosis occurred (see also table 5). The results indicate that the amount of the therapeutic concentrates received was not related to the evolution towards AIDS. 39% of the group III patients had developed AIDS, while this only happened in 10% of group VI patients (the most treated).

prognostic marker of a bad evolution can be the kind of infection or the tumor the patient is suffering from. Only 21 out of 49 deaths were due to infec­ tion or tumor which allowed us to make an AIDS diagnosis. For instance, none of the 20

Table 9. Development of AIDS in the different groups

Amount o f Antihemophilic Concentrate Received and Deaths The patients treated with the highest amounts of concentrate do not seem to be those who suffered the worst progression (ta­ ble 13). When the patients were classified ac­ cording to age (table 14), we can see that the oldest patients (> 35 years) had a bad progno­ sis, without relation to treatment. According to table 15, it is very probable that the best

Group

AIDS patients, %

II III IV V VI

50a 39 7 22 10

a There were only 2 patients in this group.

Table 10. AIDS death rates among the Spanish seropositive population and patients infected by blood and blood derivatives

Diagnosed

Spain Total number Recipients of

Blood transfusions Hemoderivatives Hemophilia Center La Paz Hemophiliacs

Table 11. Deaths rate related to the age of the patients

Age years

Dead

< 17 18-34 >35

14 20 15

Dead n

%

10,101 117 303

3,989 89 167

39 53 55

95

49

51

AIDS diagnosed

Séropositives

n

% of deaths

n

24 44 27

58 45 55

77 127 53

% of deaths 18 16 28

287

Downloaded by: Nagoya University 133.6.82.173 - 1/15/2019 12:47:48 AM

CD4 Lymphocyte Levels in Relation to Death Rate When we compare these levels at the time of diagnosis among the patients who later died with those of AIDS patients and those of asymptomatic seropositive patients, we can see (table 12) that there is not any significant difference which allows us to obtain conclu­ sions from the point of view of prognostic markers of progression of the disease.

Table 12. Death rate related to CD4 levels

CD4/mm;,

> 500 200-500 100-200 < 100

AIDS patients, % dead

alive

0 13 22 64

2 16 20 61

Table 14. AIDS development (%) related to age and therapeutic group

Seropositive patients, %

Group

16 37 22 10

III IV V VI

Table 13. Death rate related to the amount of anti­ hemophilic concentrate received

Age, years < 17

17-34

25

62

-

-

20 25

27 66

>35 100 -

50

Table 15. Causes of death

n

III IV V VI

AIDS patients total (% of séropositives)

dead (% of AIDS patients)

39 7 22 10

64 0 30 43

patients in whom the initial diagnosis was esophageal candidiasis died because of it. The initial causes with the worst prognosis, ac­ cording to our experience, are shown in ta­ ble 16.

Effects of the Therapeutic Approaches

The survival of AIDS patiens had im­ proved lately thanks to different measures: (1) administration of zidovudine; (2) earlier diagnosis and more efficient treatment of the opportunistic infections, and (3) primary and secondary prevention of different opportunis­ tic infections.

288

P. carinii pneumonia Neurological complications Pneumonias other than P. carinii Constitutional disease Lymphomas Disseminated cytomegalovirus infection Cryptosporidium diarrhea Decompensated hepatopathy Unknown

13 13 9 4 3 3 2 2 1

In our experience, the prolongation of time between diagnosis and death can be attrib­ uted to zidovudine. Before zidovudine treat­ ment of 18 patients, this time ranged from 2 to 652 days (average 7 months and 16 days). With zidovudine treatment of 18 patients, the time ranged from 181 to 1,061 days (average 23 months and 18 days). We found similar results as those de­ scribed in the international literature [12-14] for patients who had taken Retrovir during a 12-month period: (1) a decrease in the num­ ber of opportunistic infections; (2) an increase of body weight; (3) a transitory elevation of CD4 levels; (4) an improvement in the neu­ ropsychological parameters; (5) in many cases

Magallôn Martinez/Ortega/Pinilla

AIDS and Hemophilia

Downloaded by: Nagoya University 133.6.82.173 - 1/15/2019 12:47:48 AM

Group

Table 17. Patient survival studied at 6-month in­ tervals related to zidovudine intake

Cause of AIDS

Deaths % of the cases

Survival time months

Lymphomas Cytomegalovirus Meningeal cryptococcosis HIV encephalopathy Constitutional disease Cerebral toxoplasmosis Cryptosporidium diarrhea P. carinii pneumonia

100 100 100 75 66 50 50 44

the development of anemias and granulocyto­ penias as a sign of a toxic reaction; (6) an improvement in the thrombocyte counts; (7) no increase in the hemorrhagic morbidity, and (8) that high doses were not more effec­ tive than the lower ones. Time has proved that these initial hopeful results have not been constant [15-17] and that after 15-18 months the symptoms reap­ pear. Therefore, when we study the survival at 6-month periods, we can observe that only 33% of the patients survived for 36 months (table 17). We are initiating some clinical assays using the new antiretroviral drug ddl which seems to be effective against HIV [18-20], but the selection criteria are so rigorous that only a small number of patients will be able to par­ ticipate. At present, following international sugges­ tions [21-26], our attitude towards the HIV­ positive hemophilia patients is: (1) patients with CD4 levels > 500/mm3: periodical sur­ veillance every 6-9 months; (2) asymptom­ atic patients with CD4 levels between 200 and 500/mm3: (a) with stable counts: periodical surveillance every 3-6 months (the possibility of the Retrovir therapy is discussed with the

Up to 6 Up to 12 Up to 18 Up to 24 Up to 30 Up to 36

Not treated ( n - 18)

T reated with zidovudine (n = 18)

n

%

n

%

5 4 1 0 0 0

28 23 8 0 0 0

18 17 16 13 10 6

100 94 89 72 55 33

patients, and once they are informed, a deci­ sion concerning the treatment is taken) and (b) with decreasing counts: revision on a 2month basis and comments related to the aforementioned treatment; (3) patients with HIV-related symptoms and signs or HIVrelated thrombocytopenia unrelated to the CD4 levels: Retrovir therapy is recom­ mended; (4) patients with CD4 levels < 200/mm3: we recommend Retrovir and P. carinii prophylaxis [27] (in our center aerosol­ ized pentamidine in 90% of the cases), and (5) patients belonging to group IV according to the Center for Disease Control: as in sec­ tion 4. The initial doses of Retrovir presently used range form 500 to 600 mg/day (200 mg every 4 h respecting sleep or 200 mg every 8 h). During the first 6 weeks the patient is fol­ lowed up every fortnight, and if he remains stable every month. Finally, in an attempt to discover some relationship between the patients’ previous situation and the development of AIDS under the influence of zidovudine, we have classi­ fied the patients who have taken this drug, according to age, into three categories: (1) 22 AIDS patients still alive; (2) 20 dead AIDS patients, and (3) 42 asymptomatic patients

289

Downloaded by: Nagoya University 133.6.82.173 - 1/15/2019 12:47:48 AM

Table 16. Causes of AI DS with the worst prognosis among the La Paz Hemophilia Center patients

Table 18. Patients treated with zidovudine classi­ fied according to diagnosis and age

Total

AIDS Dead Alive Asymptomatic

22 20 42

Age, years 35

7 2 4

11 11 29

4 7 9

Table 19. CD4 levels per cubic millimeter before and after zidovudine treatment

Alive patients Dead patients Asymptomatic patients

Previous test

Latest test

100 ± 104 113 ± 110 138 ±114

63 ±74 54 ±92 127 ± 133

(table 18). The following parameters were in­ vestigated: (1) the length of time since the diagnosis of AIDS; (2) the period of time tak­ ing zidovudine; (3) antigenemia p24; (4) CD4 levels, and (5) blood cell counts. Length o f Time Since the Diagnosis o f AIDS The average values are expressed in months. Alive patients: 23.5 ± 12.6; dead patients: 26.2 ± 18.2. There was no statisti­ cally significant difference. Period o f Time Taking Zidovudine The average values are also shown in months. Alive patients: 21.8 ± 12.7; dead patients: 20.5 ± 10.6; asymptomatic patients: 15.2 ± 13.1. There was no statistically signifi­ cant difference.

Table 20. Hematological parameters before zidovudine treatment

Patients

Hemoglobin, g/dll Leukocytes, X 109/1 Granulocytes, X 109/1 Lymphocytes, X 109/1 Platelets, X 109/1

alive

dead

asymptomatic

12.7 ± 1.6 3.6 ±1.2 1.8 ±0.9 1.0 ± 0.6 168 ±90

12.8 ± 1.9 3.4± 1.8 1.1 ± 1.0 0.9 ±0.9 136 ±57

13.9 ± 1.7* 4.3 ± 1.7* 2.2 ±1.1 1.5±0.8* 167 ±79

* p < 0.05 between alive-dead and asymptomatic patients.

Hemoglobin, g/dl Leukocytes, X 109/1 Granulocytes, X 109/1 Lymphocytes, X 109/1 Platelets, X 109/1

alive

dead

asymptomatic

12.6± 1.6 3.1 ±1.1 1.5 ±0.7 0.8 ±8.0 209 ±62**

11.7 ± 1.6 3.0± 1.0 1.7± 1.2 0.8 ± 1.1 125 ± 56

13.2 ± 1.3* 3.8 ±1.5 1.8 ± 1.0 1.2±0.7* 196 ± 96**

* p < 0.05 between alive-dead (symptomatic) and asymptomatic patients; ** p < 0.05 between dead and alive-asymptomatic patients.

290

Magallon Martinez/Ortega/Pinilla

AIDS and Hemophilia

Downloaded by: Nagoya University 133.6.82.173 - 1/15/2019 12:47:48 AM

Table 21 . Hematological parameters according to last test

Antigenemia p24 During the data collection, we took into account the fact that the patients presented antigenemia, despite its presence being transi­ tory. We detected the p24 antigen, by using the western blot test, in the following percent­ ages: dead patients: 22; alive patients: 32; asymptomatic patients: 22; asymptomatic pa­ tients who developed AIDS: 64. The similar­ ity in the percentages of the first three groups is remarkable. The high incidence among the asymptomatic patients who developed AIDS underlines the concept that it is a bad prog­ nostic marker, although the patients were tak­ ing zidovudine. CD 4 Levels Table 19 shows the average CD4 levels ac­ cording to the tests performed before and the last test after zidovudine treatment. There was only a statistically significant difference between the latest levels of asymptomatic and dead patients. The difference after the treat­ ment among symptomatic and asymptomatic patients is remarkable. Blood Cell Counts The levels of hemoglobin and the absolute counts of leukocytes, granulocytes, lympho­

cytes, and platelets were eveluated before treatment and compared among the three pa­ tient groups as shown in table 20. There was only a statistically significant difference in the hemoglobin levels and leukocyte and lympho­ cyte counts among the asymptomatic and the alive/dead patients. The same parameters were also investi­ gated and compared according to the last tests done (table 21). According to the results, the asymptomatic patients presented higher lev­ els of hemoglobin, lymphocytes, and platelets, with statistical significance, than the symp­ tomatic patients. From these results, very similar to those of other autors [28-29], we could conclude: (1) the toxicity related to zidovudine is less serious among the asymptomatic patients; (2) long-term zidovudine treatment is unable to stop the decrease of lymphocyte and CD4 lymphocyte levels among the AIDS patients; (3) the decrease of CD4 lymphocyte levels among the AIDS patients is not a trustworthy prognostic marker; (4) all patients studied showed low granulocyte levels unrelated to the clinical status, and (5) zidovudine is un­ able to modify the progression of disease in HIV-seropositive asymptomatic patients with antigenemia.

1 Magallón M, Martin Villar J, Ortega F: Status VIH en hemofílicos: Expe­ riencia de tres años en el trata­ miento con productos tratados por calor. Sangre (Bare) 1987;32:394395. 2 Lee CA, Philips AN, Elford J, Miller EJ, Bofill M, Griffiths PD, Kernoff PBA: The natural history of human immunodeficieny virus infection in a hemophilic cohort. Br J Haematol 1989;73:228-234.

3 Darby SC, Rizza CR, Doll R, Spooner RJD, Stratton JM, Tahkrar B: Incidence of AIDS and excess of mortality associated with HIV in Haemophiliacs in the U.K. Report on behalf of the directors of hemo­ philia centres in the U.K. Br M J 1989;289:1064-1068.

4 Lee CA, Phillips AN, Elford J, Janossy G, Griffiths P, Kernoff P: Pro­ gression of HIV disease in a haemophilic cohort followed for 11 years and the effect of treatment. B M J 1991;303:1013-1096. 5 Ragni MV: The natural history of HIV infection in hemophilia; in Lusher JM, Kessler OM (ed): Hemo­ philia and von Willebrand’s disease in the 1990s. Amsterdam, Elsevier, 1991, pp 383-388.

291

Downloaded by: Nagoya University 133.6.82.173 - 1/15/2019 12:47:48 AM

References

6 Eyster ME, Gail MH, Ballard JO, AL-Mondhisy H, Goedert JJ: Natu­ ral history of human immunodefi­ ciency virus infection in hemophil­ iacs: Effects of T cell subsets, plate­ let counts and age. Ann Intern Med 1987;107:1-6. 7 Goedert JJ, Kessler CM, Aledort LM, Biggar RJ, Andes WA, White GC, Drummond JE, Vaidya K, Mann DL, Eyster ME, Ragni MV, Lederman MM, Cohen AR, Bray GL, Rosenberg PS, Friedman RM, Hilgartner MW, Blattner WA, Kroner B, Gail MH: A prospective study of human immunodeficiency virus type 1 infection and the devel­ opment of AIDS in subjects with hemophilia. N Engl J Med 1989; 321:1141-1148. 8 Eyster ME, Ballard JO, Gail MH, Drummond JE, Goedert JJ: Predic­ tive markers for the acquired immu­ nodeficiency syndrome (AIDS) in hemophiliacs: Persistence of p24 an­ tigen and low T4 cell count. Ann Intern Med 1989;110:963-969. 9 Schiriain N, Ghirardini A, Chiarotti F, Gringeri A, Mannucci PM, and the Italian Group: Progression to AIDS among Italian HIV seroposi­ tive haemophiliacs. AIDS 1991 ;5: 385-391. 10 Tsoukas CM: Surrogate markers of HIV disease progression in persons with hemophilia and human immu­ nodeficiency virus infection; in Lusher JM, Kessler OM (eds): He­ mophilia and von Willebrand’s dis­ ease in the 1990s. Amsterdam, Else­ vier, 1991, pp 413-419. 11 Simmonds P, Beatson D, Cuthbert RJ, Watson H, Parry JV, Steel CM, Peutherer JF, Reynolds B, Ludlam CA: Determinants of HIV disease progression: Six year longitudinal study in the Edinburgh Haemo­ philia HIV Cohort. Lancet 1991; 338:1 159-1163. 12 Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volderbing PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Schooley RT, Jackson GG, Durack DT, Phil D, King D, and the AZT Collaborative Working Group: The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDSrelated complex: A double-blind placebo-controlled trial. N Engl J Med 1987;317:185-191.

13 Richman DD, Fischl MA, Grieco MH, Gottlieb MS, Volderbing PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Hirsch MS, Jackson GG, Durack DT, Phil D, NusinoffLehrman S, and the AZT Collabora­ tive Working Group: The toxicity of azidothymidine (AZT) in the treat­ ment of patients with AIDS and AIDS-related complex. A double­ blind placebo-controlled trial. N Engl J Med 1987;317:192-197. 14 Fischl MA, Parker CB, Pettinelli C, Wulfshon M, Hirsch MS, Collier AC, Antoniskis D, Ho M, Richman DD, Fuchs E, Merigan TC, Reichman RC, Gold J, Steigbigel N, Leoung GS, Rasheed S, Tsiatis A, and The AIDS Clinical Group: Ran­ domized controlled trial of a re­ duced daily dose of zidovudine in patients with the acquired immu­ nodeficiency syndrome. N Engl J Med 1990;323:1009-1014. 15 Fischl MA, Richman DD, Causey DM, Grieco MH, Bryson Y, Mild­ van D, Laskin OL, Groopman JE, Volberding PA, Schooley RT, Jackson GG, Durack DT, Andrews JC, Nusinoff-Lehrman S, Bassry DW, and the AZT Collaborative Working Group: Prolonged zidovudine ther­ apy in Patients with AIDS and ad­ vanced AIDS-related complex. JAMA 1989;262:2405-2410. 16 Larder BA; Darby G, Richman DD: HIV reduced sensivity to zidovu­ dine (AZT) isolated during pro­ longed therapy. Science 1989;243: 1731-1734. 17 RookeR, Tremblay M,SoudeynsH: Isolation of drug-resistant variant of HIV-1 from patients on long-term zidovudine therapy. AIDS 1989;3: 411-415. 18 Yarchoan R, Mitsuya H, Thomas RV, Pluda JM, Hartman NR, Pernd CF, Marcyk KS, Allain JP, Johns DG, Broder S: In vivo activity against HIV and favorable toxicity profile of 2-3-dideoxyinosine. Science 1989;245:412-415. 19 Yarchoan R, Pluda JM, Thomas RV, Mitsuya H, Brouwers P, Wyvill KM, Hartman A, Johns DG, Broder S: Long-term toxicity/activity pro­ file of 2-3-dideoxyinosine in AIDS or AIDS-related complex. Lancet 1990;336:526-529.

20 Lambert JS, Sidlin M, Reichman CR, Plank CS, Laverty M. Morse GD, Knupp C, McLaren C, Petti­ nelli C, Valentine FT, Dolin R, and the AIDS Clinical Group: 2-3-Dideoxyinosine (ddl) in patients with the acquired immunodeficiency sindrome or AIDS-related complex. N Engl J Med 1990;322:1333-1340. 21 Editorial: Clinical trials of zidovu­ dine in HIV infection. Lancet 1989; 333:483-484. 22 Editorial: Zidovudine in symptom­ less HIV infection. Lancet 1988; 335:415-416. 23 Editorial: Zidovudine for symptom­ less HIV infection. Lancet 1990;i: 821-822. 24 Swart AM, Weller I. Darbyshirc JM: Early HIV infection: To treat or not to treat? BMJ 1990;301:825-826. 25 Friedland GH: Early treatment for HIV. N Engl J Med 1990;322:1000-

292

Magallón Martinez/Ortega/Pinilla

AIDS and Hemophilia

1002.

Downloaded by: Nagoya University 133.6.82.173 - 1/15/2019 12:47:48 AM

26 Klein RS: Zidovudine for HIV in­ fection without symptoms. Lancet 1990;335:1228. 27 Editorial: Guidelines for prophy­ laxis against pneumocystis carinii pneumonia for persons infected with human immunodeficiency vi­ rus. MMWR 1989;38:1-9. 28 Volberding PA, Lagakos SW, Koch MA, Pettinelli C, Myers MW, Both DK, Balfour HH, Reichman RC, Bartlett JA, Hirsch MS, Murphy RL, Hardy WD, Soeiro R, Fischl MA, Bartlett JG, Merigan TC, Hyslop NE, Richman OD, Valentine FT, Corey L: Zidovudine in asymp­ tomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CD4 positive cells per cubic millimeter. N Engl J Med 1990;322:941-949. 29 Corzo JE, Leal M: Zidovudina e in­ fección por el virus de la immunodeficiencia humana: Cuándo y cómo iniciar el tratamiento. Med Clin (Bare) 1991;97:178-180.

AIDS and hemophilia: experience in the La Paz Hemophilia Center.

435 hemophiliacs are usually being attended in the La Paz hemophilia Center (Madrid, Spain). 257 (59%) of these patients have been infected by the hum...
2MB Sizes 0 Downloads 0 Views