1541
completely well, happy, and free of symptoms. She could sit ina for as long as was necessary. This woman is one of many such patients of all ages, and although it is not always easy to wean patients from their tablets, it can usually be done with appropriate support and explanation. Why has it taken the profession such a long time to realise this?4 These patients become some of the most grateful a doctor can have. was
car
8 Linnell Drive, London NW11 7LT, UK
SAMUEL I. COHEN
1. Ashton H. Benzodiazepine withdrawal, an unfinished story. BMJ 1984; 288: 1135-40. 2. Stockwell T, Smail P, Hodgson R, Canter S. Alcohol dependence and phobic anxiety states II, a retrospective study. Br J Psychiatry 1984; 144: 58-63. 3. Ogunremi OO, Adamson L, Brezinova V, et al. Two anti-anxiety drugs: a psychoneuroendocrine study. BMJ 1973; 2: 202-05. 4. Cohen SI. Are benzodiazepines useful in anxiety. Lancet 1987; ii: 1080.
An important disadvantage of re-using tests with the Genie assay is that the internal controls, which indicate that the test has been done as recommended, react after the primary testing and therefore do not allow for monitoring during the retest. This does not seem to be a problem with the SUDS test, since the control is not influenced by the initial test. Additionally, the re-use of cartridges still requires extra use of kit reagents, and will not result in significant savings unless excess reagents are supplied. The performance must be verified with a larger number of samples from both high-risk and low-risk populations before the use of these devices for re-testing can be considered fully. Department of Pathology, School of Medicine, University of Maryland, Baltimore, Maryland 21201, USA
XIANG ZHANG NIEL T. CONSTANTINE JAYA BANSAL
1. Constantine
Rapid HIV tests: two for the price of one SIR,-Rapid HIV tests have been commercially available for over 4 years, but their use has not gained in popularity because of their high cost ($US3-12 each).1 HIV testing on alternative body fluids, such as urine and saliva,2-4 and the testing of pooled serums and urine (our data) have been explored in an effort to decrease the cost of the overall testing process (ie, blood collection). We report cost savings by re-use of cartridges after the testing of samples that did not contain antibodies to HIV. Two panels of 60 HIV confirmed positive and 40 HIV negative sera from individuals in the USA and Central Africa were tested with two rapid HIV assays immediately after the testing of HIV negative samples by the same device. In addition, two HIV seroconversion panels (Serologicals, Inc) were used to assess the sensitivity of the re-used tests. Assays included the SUDS (Murex) and Genie (Genetic Systems) microparticle filtration tests. Both of these tests incorporate mixtures of viral lysates and synthetic peptides of HIV, and are done in 10 min or less. Both tests accurately identified all HIV positive and negative sera, even though the devices had been used before to test HIV negative samples. In general, reactivities were equivalent to those obtained with the devices used once only. However, the SUDS test required that the reaction time be extended to 4 min, rather than the recommended 2 min when testing samples only once. The Genie test required that the prefilter be replaced before addition of the second sample. Both tests were modified by replacing stop solution with an extra wash between samples. When testing the seroconversion panel, both tests had expected reactivities; the SUDS test detected seroconversion up to 11days before a routine enzyme-linked immunosorbent assay (ELISA) (table). None of the re-used tests from either manufacturer produced any false-positive reactions when testing HIV negative sera. Each device can be used up to five times (SUDS) with negative sera, and still perform adequately in the detection of positive sera. Preliminary results of this retesting with the HIV-1/2 dipstick (PATH) and the HIV-1 /2 Test Pack (Abbott) are also encouraging. The re-use of rapid test devices offers significant savings, potentially decreasing the cost by at least half. This saving would be best achieved when testing samples from a low-risk population, in which most samples are negative. The use of rapid assays could be effective for epidemiological studies, especially in areas where the capacity for ELISA testing does not exist. RE-USE OF RAPID TEST CARTRIDGES WHEN TESTING TWO HIV SEROCONVERSION PANELS
*Results
(OD/CO) provided by Serologicals,
Inc
NT, Callahan JD, Watts DM. Retroviral testing: essentials for quality control and laboratory diagnosis. CRC Press, 1992. 2. Connell JA, Parry JV, Mortimer PP, et al. Preliminary report: accurate assays for ann-HIV m urine. Lancet 1990; 335: 1336-69. 3. Archibald DW, Johnson JP, Nair P, et al. Detection of salivary immunoglobulin A antibodies to HIV-1 in infants and children. AIDS 1990; 4: 417-20. 4. Akker RVD, Hoek ARVD, Akker WMRVD, et al. Detection of HIV antibodies in saliva as a tool for epidemiological studies. AIDS 1992; 6: 953-57. 5. Mitchell S, Mboup S. HIV testing. In: The handbook for AIDS prevention in Africa. Family Health International, 1990:20.
Reliability of western blotting for the confirmation of HIV-1 seroconversion SIR,-Dr Zaaijer and colleagues (Sept 26,
p 770) reported the third-generation enzyme immunoassays (EIAs) and the poor sensitivity of western blot (WB) for the detection of anti-HIV-1antibodies during seroconversion. We present data that raise further doubts about the reliability of WB as a confirmation
value of
for HIV-1 infection. Between April, 1990, and October, 1992, we followed the timing of seroconversion in twenty-seven patients. In eight of these, all of whom had symptoms, the first available serum samples (n = 11) were negative by WB (New Lav Blot 1, Diagnostics Pasteur, and WB HIV-1 Biotech/Ortho Diagnostic), but contained neutralisable p 24 antigen (Abbott polyclonal EIA) or were repeatedly positive with at least one EIA test, or both. 10 of the 11 samples were positive for p24 antigen; the other sample remained negative after acid dissociation. Later sequential samples from these eight patients showed a characteristic seroconversion pattern in V.7B; the mean time to appearance of the first bands (gp 160-p 24) was 7-7 (4-1) days. The table shows the sensitivity of two indirect first-generation EIA tests (Rapid Elavia Mixt, Diagnostics Pasteur; HIV Mixt, Organon Teknica), four indirect second-generation tests based on recombinant antigens (Genelavia Mixt, Diagnostics Pasteur; Abbott HIV-ljHIV-2) or synthetic peptides (Enzygnost HIV-1/ HIV-2, Behring; Clonatec HIV-1/HIV-2), a second-generation competitive test (Wellcozyme Rec HIV-1, Murex), and two direct third-generation sandwich tests (Abbott HIV-ljHIV-2 3rd G, Wellcozyme HIV-1/HIV-2) for anti-HIV-1 antibodies in the 11 serum samples. Neither first-generation EIA test was positive, and the second-generation tests based on recombinant antigens were positive in only one patient (Abbott HIV-1/HIV-2). Both secondgeneration tests based on synthetic peptides were positive in three patients. The third-generation tests were highly sensitive since both were positive for 6 of the 11 samples, and gave reproducible overflow reactivity in 2 of these. In patient 5, only the thirdgeneration EIA Wellcozyme HIV-1/HIV-2 test was positive. The competitive EIA was most sensitive in patient 1, since it revealed specific antibodies before the third-generation tests. 3 samples remained negative with all EIA tests; the only marker of infection was serum p24 antigen; the EIA antibodies tests became positive only after 1, 4, and 5 days (patients 3, 4, and 7). These results suggest that WB lacks sensitivity during seroconversion and should no longer be regarded as the gold standard for serological diagnosis of HIV infection. The poor reliability of WB for the detection of anti-HIV-1 antibodies has been pointed out by Mortimer.’ Furthermore, although thirdgeneration tests are the most sensitive, none of the EIA tests for test
1542
WB-NEGATIVE SERUM SAMPLES FROM EIGHT HIV-1
EAR LYSEROCONVERTERSTESTED BY DIFFER ENTG EN ERATIONS OF EIA
apparent difference in resting saliva production between their patients receiving didanosine and those not may be due to the effect
of stage of HIV infection rather than the effect of didanosine. Dodd and colleagues suggest that didanosine is exerting its effect on resting salivary flow by causing a neuropathy which reduces the normal sympathetic flow to the gland. Although it is a possible
mechanism, we think that it is more likely that the effect is more analogous to the well-documented effect of didanosine on the pancreas, which is histologically similar to salivary tissue. The same mechanism that causes xerostomia may be interferring with resting pancreatic flow, which predisposes patients receiving didanosine to
pancreatitis. We agree with Dodd and colleagues that although xerostomia seem to be a trivial side-effect of an antiretroviral agent, its deleteriouis impact on the quality of life for an individual may be considerable but rarely necessitates withdrawal of the drug. Our experience of treating this side-effect has been that present remedies are disappointing, but fortunately this side-effect is much less common than the 35% reported by Dodd et al. may
are highest optical density/cut-off ratio obtained for each category of test. Positivity criteria = ratio;;.1 Rec=recombinant antigens; SP=synthetic peptide antigens, compet =competitive assay (cut-off/optical density ratio), neg =negative. *All first samples positive for neutralisable p24 antigen and/or repeatedly positive in at least one EIA test for anti-HIV-1 antibodies; +days=time between two samples.
Results
antigens or antibodies used alone is sufficient to diagnose primary HIV-1 infection. As a result, the detection and conrmation of HIV-1 infection should be based on the use of several EIA tests, together with the detection of p24 antigen during the initial phase of primary HIV-1infection. Our results favour the association of sandwich and competition ElAs, which both detect immunoglobulins of various isotypes. In addition, after seroconversion, the high specificity of competitive assays means that they provide an indication as to the HIV serotype at the same time as the diagnosis.2
FRANÇOIS SIMON
Virology Department, Hôpital Bichat-Claude Bernard,
JEAN MICHEL PÉPIN
75877 Paris, France
FRANÇOISE BRUN-VEZINET
Infectious Diseases Departments, Hôpital Bichat-Claude Bernard, Paris
HENRIQUE CASALINO
OLIVIER BOUCHAUD LAURENCE GÉRARD
1. Mortimer PP. The fallibility of HIV western blot. Lancet 1991; 337: 286-87. 2. Simon F, Meana A, Rinaldi R, et al. HIV-1 competitive ELISA for serological diagnosis of HIV-2 positivity. AIDS 1990; 4 1169-70.
Xerostomia associated with didanosine SIR,-Ms Dodd and colleagues’ (Sept 26, p 790) report of xerostomia in association with didanosine treatment contains inaccuracies. Xerostomia has been reported previously-indeed, two of the references they cite document this side-effect of didanosine. Other phase 1/11 studies, which they do not cite, and larger phase III studies have also reported this effect.3 The true incidence of xerostomia associated with didanosine, however, is probably considerably less than the 35% figure suggested by Dodd and colleagues. In the MRC/ANRS Alpha study of didanosine, which is the largest, and continuing, randomised trial of didanosine monotherapy in HIV-positive patients, the frequency of subjective xerostomia is only 98%, despite the possibility -of this side-effect being brought to the attention of trial participants and their clinicians 4,5It is by no means certain that xerostomia seen in Dodd’s study population is due to didanosine. Xerostomia has been reported as a feature of HIV infection6 and indeed their group has previously reported salivary gland abnormalities in HIV-positive patients before didanosine was in clinical use.7 In the USA didanosine is licensed for combination therapy for patients intolerant of or failing on zidovudine. Such patients will usually have a more advanced stage of HIV infection in which there may be a higher incidence of xerostomia. Data presented at the VIIIth International Conference on AIDS suggest that this effect is due to the drug rather than stage of infection. Dodd and colleagues do not indicate whether their study design allowed them to address the question of whether the
MRC HIV Clinical Trials Centre, Department of Clinical Epidemiology, Royal Brompton National Heart and Lung London SW3 6NP, UK
Department of Biochemistry, Kings College Hospital, London SE5
Hospital,
CHRIS VALENTINE
JEAN DEENMAMODE ROY SHERWOOD
R, Pluda JM, Thomas RV, et al. Long term toxicity/activity profile of 2’3’-dideoxyinosine in AIDSor AIDS-related complex. Lancet 1990; 336: 526-28. 2. Rozencweig M, McClaren C, Beltangady M. Overview of phase I trials 2’3’ -dideoxyinosine (ddI) conducted on adult patients. Rev Infect Dis 1990; 12: 1. Yarchoan
S570-75. 3. Nelson M, Moyle G, Reddy T, et al. Toxicity of dideoxyinosine (ddI) in zidovudine intolerant patients. Presented at VII International Conference on AIDS, Florence, June, 1991 (abstr no WB 2111). 4. Valentine C, Sherwood R, Deenmamode J. Didanosine and amylase monitoring. Lancet 1992; 339: 999. 5. Sweeney I, Valentine C, Gompels M, et al. Nucleoside analogues and patterns of salivary, pancreatic and total amylase in HIV positive individuals. Presented at VIII International Conference on AIDS, Amsterdam, July, 1992 (abstr no MoB
0078). 6. Kame BR. Rheumatologic manifestations of infection with human immunodeficiency virus (HIV). Ann Intern Med 1989; 111: 158-67. 7. Schiodt M, Greenspan D, Daniels TE, et al. Parotid gland enlargement and xerostomia associated with labial sialadenitis in HIV infected patients. J Autoimmun 1989; 2: 415-25.
This letter has been shown to Ms Dodd and colleagues, whose reply follows.-ED. L. SIR,-Dr Valentine and colleagues correctly point out that several studies have documented that didanosine is associated with
subjective xerostomia. The term xerostomia can be applied in three ways: as a symptom of oral dryness; as the clinical sign of oral dryness (mucosal fissures, absence of pooled saliva, and a failure to express saliva from the major gland ducts on palpation); and as a reduction in objectively measured unstimulated whole salivary or stimulated parotid flow. The studies cited by Valentine et al allude only to subjective complaints of xerostomia, whereas in our study we measured salivary flow. The prevalence of subjective xerostomia associated with didanosine has varied between studies and may be less than the 35 % suggested by our colleagues and cited in our letter. The point of our study was that we sought to document xerostomia (dry mouth) by objective measurements of salivary flow. These measurements were of unstimulated whole salivary flow and parotid salivary flow when stimulated with citric acid solution. We showed a significant decrease in the whole salivary flow, but, surprisingly, the reduction in stimulated salivary flow was not significant. Some patients without subjective xerostomia proved to have reduced salivary flow rates. All 14 HIV-infected patients included in our sample were taking didanosine either as part of a phase II study or on a named-patient basis. Patients were excluded from the study if they met the diagnostic criteria for HIV-associated salivary gland disease.’,’ They were also excluded if they were taking other medications known to cause xerostomia, if they had received radiation therapy to the head or neck, or if they had a history of Sjogren’s syndrome. For
completely well, happy, and free of symptoms. She could sit ina for as long as was necessary. This woman is one of many such patients of all ages, and although it is not always easy to wean patients from their tablets, it can usually be done with appropriate support and explanation. Why has it taken the profession such a long time to realise this?4 These patients become some of the most grateful a doctor can have. was
car
8 Linnell Drive, London NW11 7LT, UK
SAMUEL I. COHEN
1. Ashton H. Benzodiazepine withdrawal, an unfinished story. BMJ 1984; 288: 1135-40. 2. Stockwell T, Smail P, Hodgson R, Canter S. Alcohol dependence and phobic anxiety states II, a retrospective study. Br J Psychiatry 1984; 144: 58-63. 3. Ogunremi OO, Adamson L, Brezinova V, et al. Two anti-anxiety drugs: a psychoneuroendocrine study. BMJ 1973; 2: 202-05. 4. Cohen SI. Are benzodiazepines useful in anxiety. Lancet 1987; ii: 1080.
An important disadvantage of re-using tests with the Genie assay is that the internal controls, which indicate that the test has been done as recommended, react after the primary testing and therefore do not allow for monitoring during the retest. This does not seem to be a problem with the SUDS test, since the control is not influenced by the initial test. Additionally, the re-use of cartridges still requires extra use of kit reagents, and will not result in significant savings unless excess reagents are supplied. The performance must be verified with a larger number of samples from both high-risk and low-risk populations before the use of these devices for re-testing can be considered fully. Department of Pathology, School of Medicine, University of Maryland, Baltimore, Maryland 21201, USA
XIANG ZHANG NIEL T. CONSTANTINE JAYA BANSAL
1. Constantine
Rapid HIV tests: two for the price of one SIR,-Rapid HIV tests have been commercially available for over 4 years, but their use has not gained in popularity because of their high cost ($US3-12 each).1 HIV testing on alternative body fluids, such as urine and saliva,2-4 and the testing of pooled serums and urine (our data) have been explored in an effort to decrease the cost of the overall testing process (ie, blood collection). We report cost savings by re-use of cartridges after the testing of samples that did not contain antibodies to HIV. Two panels of 60 HIV confirmed positive and 40 HIV negative sera from individuals in the USA and Central Africa were tested with two rapid HIV assays immediately after the testing of HIV negative samples by the same device. In addition, two HIV seroconversion panels (Serologicals, Inc) were used to assess the sensitivity of the re-used tests. Assays included the SUDS (Murex) and Genie (Genetic Systems) microparticle filtration tests. Both of these tests incorporate mixtures of viral lysates and synthetic peptides of HIV, and are done in 10 min or less. Both tests accurately identified all HIV positive and negative sera, even though the devices had been used before to test HIV negative samples. In general, reactivities were equivalent to those obtained with the devices used once only. However, the SUDS test required that the reaction time be extended to 4 min, rather than the recommended 2 min when testing samples only once. The Genie test required that the prefilter be replaced before addition of the second sample. Both tests were modified by replacing stop solution with an extra wash between samples. When testing the seroconversion panel, both tests had expected reactivities; the SUDS test detected seroconversion up to 11days before a routine enzyme-linked immunosorbent assay (ELISA) (table). None of the re-used tests from either manufacturer produced any false-positive reactions when testing HIV negative sera. Each device can be used up to five times (SUDS) with negative sera, and still perform adequately in the detection of positive sera. Preliminary results of this retesting with the HIV-1/2 dipstick (PATH) and the HIV-1 /2 Test Pack (Abbott) are also encouraging. The re-use of rapid test devices offers significant savings, potentially decreasing the cost by at least half. This saving would be best achieved when testing samples from a low-risk population, in which most samples are negative. The use of rapid assays could be effective for epidemiological studies, especially in areas where the capacity for ELISA testing does not exist. RE-USE OF RAPID TEST CARTRIDGES WHEN TESTING TWO HIV SEROCONVERSION PANELS
*Results
(OD/CO) provided by Serologicals,
Inc
NT, Callahan JD, Watts DM. Retroviral testing: essentials for quality control and laboratory diagnosis. CRC Press, 1992. 2. Connell JA, Parry JV, Mortimer PP, et al. Preliminary report: accurate assays for ann-HIV m urine. Lancet 1990; 335: 1336-69. 3. Archibald DW, Johnson JP, Nair P, et al. Detection of salivary immunoglobulin A antibodies to HIV-1 in infants and children. AIDS 1990; 4: 417-20. 4. Akker RVD, Hoek ARVD, Akker WMRVD, et al. Detection of HIV antibodies in saliva as a tool for epidemiological studies. AIDS 1992; 6: 953-57. 5. Mitchell S, Mboup S. HIV testing. In: The handbook for AIDS prevention in Africa. Family Health International, 1990:20.
Reliability of western blotting for the confirmation of HIV-1 seroconversion SIR,-Dr Zaaijer and colleagues (Sept 26,
p 770) reported the third-generation enzyme immunoassays (EIAs) and the poor sensitivity of western blot (WB) for the detection of anti-HIV-1antibodies during seroconversion. We present data that raise further doubts about the reliability of WB as a confirmation
value of
for HIV-1 infection. Between April, 1990, and October, 1992, we followed the timing of seroconversion in twenty-seven patients. In eight of these, all of whom had symptoms, the first available serum samples (n = 11) were negative by WB (New Lav Blot 1, Diagnostics Pasteur, and WB HIV-1 Biotech/Ortho Diagnostic), but contained neutralisable p 24 antigen (Abbott polyclonal EIA) or were repeatedly positive with at least one EIA test, or both. 10 of the 11 samples were positive for p24 antigen; the other sample remained negative after acid dissociation. Later sequential samples from these eight patients showed a characteristic seroconversion pattern in V.7B; the mean time to appearance of the first bands (gp 160-p 24) was 7-7 (4-1) days. The table shows the sensitivity of two indirect first-generation EIA tests (Rapid Elavia Mixt, Diagnostics Pasteur; HIV Mixt, Organon Teknica), four indirect second-generation tests based on recombinant antigens (Genelavia Mixt, Diagnostics Pasteur; Abbott HIV-ljHIV-2) or synthetic peptides (Enzygnost HIV-1/ HIV-2, Behring; Clonatec HIV-1/HIV-2), a second-generation competitive test (Wellcozyme Rec HIV-1, Murex), and two direct third-generation sandwich tests (Abbott HIV-ljHIV-2 3rd G, Wellcozyme HIV-1/HIV-2) for anti-HIV-1 antibodies in the 11 serum samples. Neither first-generation EIA test was positive, and the second-generation tests based on recombinant antigens were positive in only one patient (Abbott HIV-1/HIV-2). Both secondgeneration tests based on synthetic peptides were positive in three patients. The third-generation tests were highly sensitive since both were positive for 6 of the 11 samples, and gave reproducible overflow reactivity in 2 of these. In patient 5, only the thirdgeneration EIA Wellcozyme HIV-1/HIV-2 test was positive. The competitive EIA was most sensitive in patient 1, since it revealed specific antibodies before the third-generation tests. 3 samples remained negative with all EIA tests; the only marker of infection was serum p24 antigen; the EIA antibodies tests became positive only after 1, 4, and 5 days (patients 3, 4, and 7). These results suggest that WB lacks sensitivity during seroconversion and should no longer be regarded as the gold standard for serological diagnosis of HIV infection. The poor reliability of WB for the detection of anti-HIV-1 antibodies has been pointed out by Mortimer.’ Furthermore, although thirdgeneration tests are the most sensitive, none of the EIA tests for test
1542
WB-NEGATIVE SERUM SAMPLES FROM EIGHT HIV-1
EAR LYSEROCONVERTERSTESTED BY DIFFER ENTG EN ERATIONS OF EIA
apparent difference in resting saliva production between their patients receiving didanosine and those not may be due to the effect
of stage of HIV infection rather than the effect of didanosine. Dodd and colleagues suggest that didanosine is exerting its effect on resting salivary flow by causing a neuropathy which reduces the normal sympathetic flow to the gland. Although it is a possible
mechanism, we think that it is more likely that the effect is more analogous to the well-documented effect of didanosine on the pancreas, which is histologically similar to salivary tissue. The same mechanism that causes xerostomia may be interferring with resting pancreatic flow, which predisposes patients receiving didanosine to
pancreatitis. We agree with Dodd and colleagues that although xerostomia seem to be a trivial side-effect of an antiretroviral agent, its deleteriouis impact on the quality of life for an individual may be considerable but rarely necessitates withdrawal of the drug. Our experience of treating this side-effect has been that present remedies are disappointing, but fortunately this side-effect is much less common than the 35% reported by Dodd et al. may
are highest optical density/cut-off ratio obtained for each category of test. Positivity criteria = ratio;;.1 Rec=recombinant antigens; SP=synthetic peptide antigens, compet =competitive assay (cut-off/optical density ratio), neg =negative. *All first samples positive for neutralisable p24 antigen and/or repeatedly positive in at least one EIA test for anti-HIV-1 antibodies; +days=time between two samples.
Results
antigens or antibodies used alone is sufficient to diagnose primary HIV-1 infection. As a result, the detection and conrmation of HIV-1 infection should be based on the use of several EIA tests, together with the detection of p24 antigen during the initial phase of primary HIV-1infection. Our results favour the association of sandwich and competition ElAs, which both detect immunoglobulins of various isotypes. In addition, after seroconversion, the high specificity of competitive assays means that they provide an indication as to the HIV serotype at the same time as the diagnosis.2
FRANÇOIS SIMON
Virology Department, Hôpital Bichat-Claude Bernard,
JEAN MICHEL PÉPIN
75877 Paris, France
FRANÇOISE BRUN-VEZINET
Infectious Diseases Departments, Hôpital Bichat-Claude Bernard, Paris
HENRIQUE CASALINO
OLIVIER BOUCHAUD LAURENCE GÉRARD
1. Mortimer PP. The fallibility of HIV western blot. Lancet 1991; 337: 286-87. 2. Simon F, Meana A, Rinaldi R, et al. HIV-1 competitive ELISA for serological diagnosis of HIV-2 positivity. AIDS 1990; 4 1169-70.
Xerostomia associated with didanosine SIR,-Ms Dodd and colleagues’ (Sept 26, p 790) report of xerostomia in association with didanosine treatment contains inaccuracies. Xerostomia has been reported previously-indeed, two of the references they cite document this side-effect of didanosine. Other phase 1/11 studies, which they do not cite, and larger phase III studies have also reported this effect.3 The true incidence of xerostomia associated with didanosine, however, is probably considerably less than the 35% figure suggested by Dodd and colleagues. In the MRC/ANRS Alpha study of didanosine, which is the largest, and continuing, randomised trial of didanosine monotherapy in HIV-positive patients, the frequency of subjective xerostomia is only 98%, despite the possibility -of this side-effect being brought to the attention of trial participants and their clinicians 4,5It is by no means certain that xerostomia seen in Dodd’s study population is due to didanosine. Xerostomia has been reported as a feature of HIV infection6 and indeed their group has previously reported salivary gland abnormalities in HIV-positive patients before didanosine was in clinical use.7 In the USA didanosine is licensed for combination therapy for patients intolerant of or failing on zidovudine. Such patients will usually have a more advanced stage of HIV infection in which there may be a higher incidence of xerostomia. Data presented at the VIIIth International Conference on AIDS suggest that this effect is due to the drug rather than stage of infection. Dodd and colleagues do not indicate whether their study design allowed them to address the question of whether the
MRC HIV Clinical Trials Centre, Department of Clinical Epidemiology, Royal Brompton National Heart and Lung London SW3 6NP, UK
Department of Biochemistry, Kings College Hospital, London SE5
Hospital,
CHRIS VALENTINE
JEAN DEENMAMODE ROY SHERWOOD
R, Pluda JM, Thomas RV, et al. Long term toxicity/activity profile of 2’3’-dideoxyinosine in AIDSor AIDS-related complex. Lancet 1990; 336: 526-28. 2. Rozencweig M, McClaren C, Beltangady M. Overview of phase I trials 2’3’ -dideoxyinosine (ddI) conducted on adult patients. Rev Infect Dis 1990; 12: 1. Yarchoan
S570-75. 3. Nelson M, Moyle G, Reddy T, et al. Toxicity of dideoxyinosine (ddI) in zidovudine intolerant patients. Presented at VII International Conference on AIDS, Florence, June, 1991 (abstr no WB 2111). 4. Valentine C, Sherwood R, Deenmamode J. Didanosine and amylase monitoring. Lancet 1992; 339: 999. 5. Sweeney I, Valentine C, Gompels M, et al. Nucleoside analogues and patterns of salivary, pancreatic and total amylase in HIV positive individuals. Presented at VIII International Conference on AIDS, Amsterdam, July, 1992 (abstr no MoB
0078). 6. Kame BR. Rheumatologic manifestations of infection with human immunodeficiency virus (HIV). Ann Intern Med 1989; 111: 158-67. 7. Schiodt M, Greenspan D, Daniels TE, et al. Parotid gland enlargement and xerostomia associated with labial sialadenitis in HIV infected patients. J Autoimmun 1989; 2: 415-25.
This letter has been shown to Ms Dodd and colleagues, whose reply follows.-ED. L. SIR,-Dr Valentine and colleagues correctly point out that several studies have documented that didanosine is associated with
subjective xerostomia. The term xerostomia can be applied in three ways: as a symptom of oral dryness; as the clinical sign of oral dryness (mucosal fissures, absence of pooled saliva, and a failure to express saliva from the major gland ducts on palpation); and as a reduction in objectively measured unstimulated whole salivary or stimulated parotid flow. The studies cited by Valentine et al allude only to subjective complaints of xerostomia, whereas in our study we measured salivary flow. The prevalence of subjective xerostomia associated with didanosine has varied between studies and may be less than the 35 % suggested by our colleagues and cited in our letter. The point of our study was that we sought to document xerostomia (dry mouth) by objective measurements of salivary flow. These measurements were of unstimulated whole salivary flow and parotid salivary flow when stimulated with citric acid solution. We showed a significant decrease in the whole salivary flow, but, surprisingly, the reduction in stimulated salivary flow was not significant. Some patients without subjective xerostomia proved to have reduced salivary flow rates. All 14 HIV-infected patients included in our sample were taking didanosine either as part of a phase II study or on a named-patient basis. Patients were excluded from the study if they met the diagnostic criteria for HIV-associated salivary gland disease.’,’ They were also excluded if they were taking other medications known to cause xerostomia, if they had received radiation therapy to the head or neck, or if they had a history of Sjogren’s syndrome. For
