Tuberculosis infection and HIV mortality — a reply
1
TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE (1996) 90,90 Correspondence Tuberculosis mortality and HIV infection I read with interest the recent article by Elliott and colleagues(1995: Tmnsactions, 89,78) which reported on the two-year survival of their cohort of tuberculosis (TB) patients with and without human immunodeficiency virus (HIV) infection in Lusaka, Zambia. Most other cohort studies of TB from sub-Saharan Africa have insisted on culture and/or histologically proven tuberculosis. Elliott et al. (Zoc. cit.) had a TB case definition which is appropriately broad and reflects the reality of African conditions where diagnostic facilities are often limited. This increasesthe ability to generalize their study, in particular to non-teaching hospitals in the region. dead, and all HIV positive subjects alive) is at all likely. In fact, the slightly higher loss among HIV positive pa- tients suggeststhe reverse, since individuals or families often move away from Lusaka (to their home villages throughout Zambia) when they become too ill to work, or if the wage earner in the family dies. If this, more probable, explanation is true, then our estimate of the ef- fect of HIV on mortality in tuberculosis patients is con- servative. Alison Elliott NationalJewish Center for Immunology and Resairaton, Medicine 5th Flair, Goodman Building 1400Jackson Street Denver, CO 80206-2761, USA 13 September 1995 Although the reality of the situation of TB control in sub-Saharan Africa is one of poor compliance and fol- low-up rates, the acceptanceof large losses to follow-up in the context. of a cohort study is not appropriate. Whilst the authors claim that, because the follow-up rates were similar in both HIV seropositive and sero- negative patients, this loss to follow-up was not relevant, I disagree. Only 71% of HIV seropositive and 72% of seronegative patients achieved follow-up to death or 2 years. Of those not known to have died, only 52% of HIV seropositives, compared with 68% of seronegatives, were followed for 2 years. These large lossesentail a sub- stantial potential for selection bias in the study. By using the figures in Table 2 of Elliott et al. (Zoc. cit., p. 79), the crude relative risk of death at 2 years was 3.90 (95% CI 1.94-787, P<O.OOl). However, if one considers the ‘worst case scenario’ whereby all the HIV seropositives who were lost to follow-up (52) were actually alive at 2 vears and all those HIV seroneeative (19) were dead. the Gevised relative risk of death-was only 1.05 (95% CI 0.74-1.48, P=O.79). These calculations include the 19 seropositive and 7 seronegative patients who were lost in the first month after enrolment but not included in the authors’ analysis. Thus, it is conceivable, though un- likelv, that HIV actually had no effect on mortality of TB patients in this study. It is uossible to achieve better follow-un rates with Af- rican TB patients. In my own recently completed cohort study of TB patients in MZUZU, Malawi, a follow-up rate of over 90% at 2 years was achieved. With meticulous referencing of patients’ addresses(work, home, village and spouse’s village) and use of community networks in the context of a well run national TB control pro- gramme, it is possible to maximize follow-up rates and thereby minimize the potential for biased results. Paul M. Kelly Department of Public Health and Community Medicine University of Sydney NSW2006 Australia ISJune 1995 Tuberculosis infection and HIV mortality - a reply We thank Dr Kelly for his comments [above] on our study of the effect of HIV on mortality in patients with tuberculosis in the urban setting of Lusaka, Zambia. We look forward to seeing the results of his similar studies in Malawi. We naturally agree that complete follow-up is the ideal for cohort studies of this kind and, like Dr Kelly, we took meticulous information about patient’s add- ressesand went to great lengths to trace defaulters, al- though with less success than he renorts among the more rural, and presumably more stable, population of Mzuzu. However. we do not think the senario which he suggests(with all lost patients who were HIV negative Guinea Bissau: association of chloroquine resistance of Plasmodium falciparum with the Tyr86 allele of the multiple drug-resistance gene Pfidrl Dr J. Cox-Singh and colleagues report (Transactions, 89, 436) that using a simple polymer&e chain reaction (PCRYrestriction fragment length nolvmomhism (RFLB) analysis, 18 ofFhe 19 chlor~quin&&stant Ma- laysian isolates of Plasmodium falciparum examined showed the Asn86Tyr mutation in the multidrug resis- tance gene analogue Pfmdrl. The high prevalence of re- sistance in that area rendered statistical analysis unhelp- ful. In a recent study in Guinea-Bissau, West Africa, where chloroquine resistance is less prevalent, we found a similar association of Pfmdrl:Tyr86 (detected by PCR/RFLP) with resistance (measured by the in vitro microtest carried out in the field with an I& cut-off point for resistance of ~l.l4~mol/L of blood, or 5.7 pmol/well). Of 16 samples showing chloroquine resis- tance, 11 had the relevant A754T mutation for Tyr86, whilst it was not found in 5 sensitive samples.This dif- ference was significant (P=O.O124, Fisher’s exact test). As reported by Cox-Singh and colleagues (Zoc. cit.), we found neither of the codon 1042 or 1246 variants in any sample. In another study in Zaria, northern Nigeria, prelimi- narilv renorted bv ADAGU et al. (1995: Transactions. 89, 132); we-found that 8 of 11 samples from chloroquine: resistant infections and 3 of 36 from chloroquine-sensi- tive infections showed the Tyr86 allele (P=O.O0007, Fisher’s exact test). Again, the codon 1042 and 1246 changes were not detected (a full account of this work has been submitted for publication). As shown by Cox-Singh and colleagues(Zoc cit.), corre- lation between presence of the mutation and resistance was certainly not lOO%, indicating that another determi- nant may h&e an auxiliary or prrmary role in determin- ing chloroquine resistance, as maintained by Wellems and co-workers (1991: Proceedings of the National Acad- emy of Sciences of the USA, 88, 3382). The Pfmdrl vari- ations mentioned above are not reliable in all areas, since in resistant Sudanese and Thai isolates (Awad-El- Kariem et al., 1992: Transactions, 86, 587; Wilson et al., 1993: Molecular and Biochemical Parasitology, 57, 151) the mutation was not reported. Nevertheless, in our 2 stud- ies quoted above, the sensitivities of resistance detection using PCR/RFLP were 688 and 72.7% respectively, and the specificities were 100 and 91.7%. We agree with Cox-Singh and colleagues that the use of PCRRFLP on blood spots will be valuable for the study of drug resistance, especially in remote areas where in z&o or microtests cannot be organized. The utility of this approach has been recently confirmed for the study of resistance to antimetabolites such as pyrimethamine (Adagu et al., 1995: Abstracts: 7th BSP Malaria Meeting, p. 33, abstract PDl; Trigg et al., 1995: ibid., p. 36, abstract PD9).
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Transcript of Tuberculosis infection and HIV mortality — a reply
TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE (1996) 90,90
Correspondence
Tuberculosis mortality and HIV infection I read with interest the recent article by Elliott and
colleagues (1995: Tmnsactions, 89,78) which reported on the two-year survival of their cohort of tuberculosis (TB) patients with and without human immunodeficiency virus (HIV) infection in Lusaka, Zambia.
Most other cohort studies of TB from sub-Saharan Africa have insisted on culture and/or histologically proven tuberculosis. Elliott et al. (Zoc. cit.) had a TB case definition which is appropriately broad and reflects the reality of African conditions where diagnostic facilities are often limited. This increases the ability to generalize their study, in particular to non-teaching hospitals in the region.
dead, and all HIV positive subjects alive) is at all likely. In fact, the slightly higher loss among HIV positive pa- tients suggests the reverse, since individuals or families often move away from Lusaka (to their home villages throughout Zambia) when they become too ill to work, or if the wage earner in the family dies. If this, more probable, explanation is true, then our estimate of the ef- fect of HIV on mortality in tuberculosis patients is con- servative.
Alison Elliott NationalJewish Center for Immunology and Resairaton, Medicine 5th Flair, Goodman Building 1400Jackson Street Denver, CO 80206-2761, USA
13 September 1995
Although the reality of the situation of TB control in sub-Saharan Africa is one of poor compliance and fol- low-up rates, the acceptance of large losses to follow-up in the context. of a cohort study is not appropriate. Whilst the authors claim that, because the follow-up rates were similar in both HIV seropositive and sero- negative patients, this loss to follow-up was not relevant, I disagree. Only 71% of HIV seropositive and 72% of seronegative patients achieved follow-up to death or 2 years. Of those not known to have died, only 52% of HIV seropositives, compared with 68% of seronegatives, were followed for 2 years. These large losses entail a sub- stantial potential for selection bias in the study. By using the figures in Table 2 of Elliott et al. (Zoc. cit., p. 79), the crude relative risk of death at 2 years was 3.90 (95% CI 1.94-787, P<O.OOl). However, if one considers the ‘worst case scenario’ whereby all the HIV seropositives who were lost to follow-up (52) were actually alive at 2 vears and all those HIV seroneeative (19) were dead. the Gevised relative risk of death-was only 1.05 (95% CI 0.74-1.48, P=O.79). These calculations include the 19 seropositive and 7 seronegative patients who were lost in the first month after enrolment but not included in the authors’ analysis. Thus, it is conceivable, though un- likelv, that HIV actually had no effect on mortality of TB patients in this study.
It is uossible to achieve better follow-un rates with Af- rican TB patients. In my own recently completed cohort study of TB patients in MZUZU, Malawi, a follow-up rate of over 90% at 2 years was achieved. With meticulous referencing of patients’ addresses (work, home, village and spouse’s village) and use of community networks in the context of a well run national TB control pro- gramme, it is possible to maximize follow-up rates and thereby minimize the potential for biased results.
Paul M. Kelly Department of Public Health and Community Medicine University of Sydney NSW2006 Australia
ISJune 1995
Tuberculosis infection and HIV mortality - a reply We thank Dr Kelly for his comments [above] on our
study of the effect of HIV on mortality in patients with tuberculosis in the urban setting of Lusaka, Zambia. We look forward to seeing the results of his similar studies in Malawi.
We naturally agree that complete follow-up is the ideal for cohort studies of this kind and, like Dr Kelly, we took meticulous information about patient’s add- resses and went to great lengths to trace defaulters, al- though with less success than he renorts among the more rural, and presumably more stable, population of Mzuzu. However. we do not think the senario which he suggests (with all lost patients who were HIV negative
Guinea Bissau: association of chloroquine resistance of Plasmodium falciparum with the Tyr86 allele of the multiple drug-resistance gene Pfidrl
Dr J. Cox-Singh and colleagues report (Transactions, 89, 436) that using a simple polymer&e chain reaction (PCRYrestriction fragment length nolvmomhism (RFLB) analysis, 18 ofFhe 19 chlor~quin&&stant Ma- laysian isolates of Plasmodium falciparum examined showed the Asn86Tyr mutation in the multidrug resis- tance gene analogue Pfmdrl. The high prevalence of re- sistance in that area rendered statistical analysis unhelp- ful.
In a recent study in Guinea-Bissau, West Africa, where chloroquine resistance is less prevalent, we found a similar association of Pfmdrl:Tyr86 (detected by PCR/RFLP) with resistance (measured by the in vitro microtest carried out in the field with an I& cut-off point for resistance of ~l.l4~mol/L of blood, or 5.7 pmol/well). Of 16 samples showing chloroquine resis- tance, 11 had the relevant A754T mutation for Tyr86, whilst it was not found in 5 sensitive samples. This dif- ference was significant (P=O.O124, Fisher’s exact test). As reported by Cox-Singh and colleagues (Zoc. cit.), we found neither of the codon 1042 or 1246 variants in any sample.
In another study in Zaria, northern Nigeria, prelimi- narilv renorted bv ADAGU et al. (1995: Transactions. 89, 132); we-found that 8 of 11 samples from chloroquine: resistant infections and 3 of 36 from chloroquine-sensi- tive infections showed the Tyr86 allele (P=O.O0007, Fisher’s exact test). Again, the codon 1042 and 1246 changes were not detected (a full account of this work has been submitted for publication).
As shown by Cox-Singh and colleagues (Zoc cit.), corre- lation between presence of the mutation and resistance was certainly not lOO%, indicating that another determi- nant may h&e an auxiliary or prrmary role in determin- ing chloroquine resistance, as maintained by Wellems and co-workers (1991: Proceedings of the National Acad- emy of Sciences of the USA, 88, 3382). The Pfmdrl vari- ations mentioned above are not reliable in all areas, since in resistant Sudanese and Thai isolates (Awad-El- Kariem et al., 1992: Transactions, 86, 587; Wilson et al., 1993: Molecular and Biochemical Parasitology, 57, 151) the mutation was not reported. Nevertheless, in our 2 stud- ies quoted above, the sensitivities of resistance detection using PCR/RFLP were 688 and 72.7% respectively, and the specificities were 100 and 91.7%.
We agree with Cox-Singh and colleagues that the use of PCRRFLP on blood spots will be valuable for the study of drug resistance, especially in remote areas where in z&o or microtests cannot be organized. The utility of this approach has been recently confirmed for the study of resistance to antimetabolites such as pyrimethamine (Adagu et al., 1995: Abstracts: 7th BSP Malaria Meeting, p. 33, abstract PDl; Trigg et al., 1995: ibid., p. 36, abstract PD9).
