Increased mortality of male adults with AIDS related to poor compliance to antiretroviral therapy in Malawi

Authors

  • Solomon Chih-Cheng Chen,

    1. Pingtung Christian Hospital, Pingtung, Taiwan
    2. Institute of Occupational Medicine and Industrial Hygiene, College of Public Health, National Taiwan University, Taipei, Taiwan
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  • Joseph Kwong-Leung Yu,

    1. Pingtung Christian Hospital, Pingtung, Taiwan
    2. Taiwan Medical Mission in Malawi, International Cooperation and Development Fund, Taipei, Taiwan
    3. College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
    4. Mzuzu Central Hospital, Ministry of Health, Mzuzu, Malawi
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  • Anthony David Harries,

    1. HIV Unit, Ministry of Health, Lilongwe, Malawi
    2. Family Health International, Arlington, USA
    3. London School of Hygiene and Tropical Medicine, London, UK
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  • Chin-Nam Bong,

    1. Pingtung Christian Hospital, Pingtung, Taiwan
    2. Taiwan Medical Mission in Malawi, International Cooperation and Development Fund, Taipei, Taiwan
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  • Rose Kolola-Dzimadzi,

    1. Mzuzu Central Hospital, Ministry of Health, Mzuzu, Malawi
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  • Teck-Siang Tok,

    1. Pingtung Christian Hospital, Pingtung, Taiwan
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  • Chwan-Chuen King,

    1. Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan
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  • Jung-Der Wang

    1. Institute of Occupational Medicine and Industrial Hygiene, College of Public Health, National Taiwan University, Taipei, Taiwan
    2. Department of Environmental and Occupational Medicine, National Taiwan University Hospital, Taipei, Taiwan
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Corresponding Author Jung-Der Wang, College of Public Health, National Taiwan University, Room 719, No. 17, Xu-Zhou Road, Taipei 10020, Taiwan. Tel.: +886 2 33228080; Fax: +886 2 23224660; E-mail: jdwang@ntu.edu.tw

Summary

Objective  To investigate the effect of gender on mortality of HIV-infected adults receiving antiretroviral therapy (ART) and its possible reasons.

Methods  A retrospective study to review the records for outcomes of adult cases receiving ART at Mzuzu Central Hospital, Malawi, between July 2004 and December 2006.

Results  Over the study period, 2838 adult AIDS patients received ART. Of these, 2029 (71.5%) were alive and still on ART, 376 (13.2%) were dead and 433 (15.3%) were lost to follow-up. Survival analysis with Kaplan–Meier estimator showed significantly higher survival rates among females than males in WHO stage 1, 2 and 3 (both < 0.0001) and borderline in stage 4 (P = 0.076). The Cox model revealed a death hazard ratio (males vs. females) of 1.70 (95% confidence interval 1.35–2.15) after controlling for WHO clinical stages, body mass index and age. More men than women were lost to follow-up in all occupations except health workers.

Conclusions  The most important reasons for a higher mortality in male patients starting ART may relate to their seeking medical care at a more advanced stage of immunodeficiency and poorer compliance with therapy. The issue needs to be addressed in scaling up ART programmes in Africa.

Abstract

Objectif:  Investiguer l’effet du sexe de l’individu sur la mortalité des adultes infectés par le VIH recevant une thérapie antirétrovirale (ART) et les raisons possibles.

Méthodes:  Etude rétrospective examinant les registres des résultats de cas d’adultes recevant des antirétroviraux à l’Hospital Central de Mzuzu au Malawi, entre juillet 2004 et décembre 2006.

Résultats:  Au cours de la période d’étude, 2838 adultes malades du SIDA ont reçu l’ART. De ceux-ci, 2029 (71,5%) étaient encore en vie et sous ART, 376 (13,2%) étaient décédés et 433 (15,3%) étaient perdus au suivi. L’analyse de survie par l’estimateur de Kaplan-Meier a montré de façon significative un taux de survie plus élevé chez les femmes que chez les hommes dans les stades 1, 2 et 3 de l’OMS (P < 0,0001) et de façon limite dans le stade 4 (P = 0,076). Le modèle de Cox a révélé un rapport de risque de décès (hommes ou femmes) de 1,70 (intervalle de confiance 95%: 1,35–2,15) après ajustement pour les stades cliniques de l’OMS, l’indice de masse corporelle et l’âge. Plus d’hommes que de femmes étaient perdus au suivi dans toutes les professions, sauf chez les agents de santé.

Conclusions:  Les principales raisons d’une mortalité plus élevée chez les patients masculins commençant l’ART pourraient être liées au recours aux soins médicaux à un stade plus avancé de l’immunodéficience et à une compliance plus faible à la thérapie. Ce problème devrait être abordé en étendant les programmes ART en Afrique.

Abstract

Objetivo:  Investigar el efecto de género sobre la mortalidad de adultos infectados con VIH recibiendo tratamiento antirretroviral (TAR) y sus posibles motivos.

Métodos:  Estudio retrospectivo para revisar los datos de resultados de casos de adultos recibiendo TAR en el Hospital Central de Mzuzu, Malawi, entre Julio 2004 y Diciembre 2006.

Resultados:  Durante el periodo de estudio, 2838 pacientes adultos con SIDA recibieron TAR. De estos, 2029 (71.5%) estaban vivos y aún recibiendo TAR; 376 (13.2%) habían muerto; y 433 (15.3%) fueron perdidos durante el seguimiento. El análisis de supervivencia con un estimador de Kaplan-Meier mostró una tasa de supervivencia significativamente más alta entre las mujeres que en hombres en estadios 1, 2 y 3 de la OMS (ambas < 0.0001) y limítrofe en estadio 4 (P = 0.076). El modelo de Cox reveló una relación de riesgo de muerte (hombres vs. mujeres) de 1.70 (95% intervalo confianza, 1.35–2.15) después de controlar para los estadios clínicos de la OMS, índice de masa corporal y edad. Más hombres que mujeres fueron perdidos durante el seguimiento en todas las ocupaciones, excepto trabajadores sanitarios.

Conclusiones:  La principal razón de una mayor mortalidad en pacientes hombres que comienzan TAR podría estar relacionada con el hecho de que buscan ayuda médica en un estadio más avanzado de inmunodeficiencia y tiene un peor cumplimiento con la terapia. Esto requeriría ser tenido en cuenta al ampliar los programas de TAR en África.

Introduction

Introduction of highly active antiretroviral therapy (ART) has greatly improved the survival outcomes of patients with AIDS, in both rich (Detels et al. 1998; CASCADE Collaboration 2000; Porter et al. 2003) and poor countries (Weidle et al. 2002; Coetzee et al. 2004; Wester et al. 2005; Ferradini et al. 2006; Lawn et al. 2006; Stringer et al. 2006; Wools-Kaloustian et al. 2006; Zachariah et al. 2006). Since the World Health Organization (WHO) launched the ‘three by five’ initiative of placing 3 million people in developing countries on ART by the end of 2005, great strides have been made, particularly in sub-Saharan Africa where 1.3 million patients had started ART by December 2006 (WHO et al. 2007).

As expected, the baseline degree of immunodeficiency, measured either by plasma viral load, CD4-lymphocyte count or WHO clinical stage, is one of the most important risk factors for a high mortality (Hogg et al. 2001; Weidle et al. 2002; Wester et al. 2005; Calmy et al. 2006; Stringer et al. 2006). Other risk factors include low body mass index (BMI) and anaemia (Calmy et al. 2006; Stringer et al. 2006). Before the introduction of ART, some cohort studies found no evidence of appreciable gender differences in disease progression either from seroconversion to AIDS or from AIDS to death (Suligoi 1997). Since the widespread scale-up of ART began, some studies have identified gender as an important factor in survival outcomes, although this finding is inconsistent (Melnick et al. 1994; Farzadegan et al. 1998; Prins et al. 1999; Hogg et al. 2001; Moore et al. 2002; Napravnik et al. 2002; Garcia de la Hera et al. 2004; Nicastri et al. 2005; Calmy et al. 2006; Ferradini et al. 2006). We therefore decided to investigate the effect of gender on mortality in adult AIDS cases started on ART at Mzuzu Central Hospital (MCH), North Malawi, and look for possible reasons.

Materials and methods

Study setting and management of antiretroviral therapy

Mzuzu Central Hospital is the main referral hospital in the northern region of Malawi, and through the Rainbow clinic, it has been providing free ART to eligible HIV-infected cases since July 2004 in accordance with the national guidelines (Libamba et al. 2005; MoH Malawi 2006).

When a patient is found to be HIV-positive, he/she is referred to the ART clinic for clinical staging. If the patient is found to be eligible for ART (assessed in WHO clinical stage 3 or 4 or with a CD4-lymphocyte count <200/mm3, if laboratory is available), he/she is asked to come with a guardian for a group counselling session about ART conducted by one of the staff of Rainbow clinic. All eligible HIV-positive cases undergo a thorough clinical assessment before starting therapy. Provided there are no contraindications, all cases are treated with a generic, fixed-dose combination of stavudine 30 (T30) or 40 mg (T40)/lamivudine 150 mg/nevirapine 200 mg (procured from Cipla, Mumbai, India, under the trade name of ‘Triomune’) in line with the Malawi national recommendations. Adults are concurrently given cotrimoxazole preventive therapy (CPT) according to the national guidelines.

Once started on ART and CPT, cases are followed up, first at 2 weeks and thereafter at 4-week intervals, with assessments and drugs distributed from the ART clinic. Characteristics and standardized treatment outcomes are recorded in ART treatment master cards and the ART registry monthly (Libamba et al. 2005). Treatment outcomes of HIV-infected cases receiving ART are classified into: (a) alive and on ART at MCH, (b) death, (c) lost to follow-up for more than 3 months (abbreviated as ‘default’), (d) stopped treatment and (e) transferred permanently to another ART clinic. In the Rainbow clinic, an electronic information system using fingerprints is maintained to identify every case at the start of therapy and during follow-up, which has been useful in ensuring the identity of cases attending follow-up at the clinic (Yu et al. 2005).

Data collection and statistical analysis

Data were collected from the ART registry on all persons started on ART at MCH, comprising age, sex, date and reason for starting ART. The outcomes for cases alive and on ART were censored on 31 December 2006. Adverse outcomes (death, treatment stop, lost to follow-up for more than 3 months and transferred out) were recorded with their dates up until the censor date of 31 December 2006. Data were entered and cleaned in EXCEL and analysed with sas statistical software (Version 8.2, SAS Institute Inc., Cary, NC, USA).

Survival analyses were conducted with Kaplan–Meier estimates and the log-rank test to compare the difference between survival functions. We also constructed a Cox proportional hazard model to estimate the hazard ratios (HR) of mortality for the prognostic factors age (every 10 years interval starting from 15 years); gender (male, female); WHO clinical staging (stages 1 and 2 with a CD4 count <200 cells/mm3, stage 3 and stage 4) and body mass index (BMI) (<17, 17–18.5 and >18.5). Results were presented as HR with 95% confidence intervals (CI).

Ethical approval

The Malawi National Health Science Research Committee does not require studies that use routine programmatic data collection to be formally submitted for ethical or scientific approval. As such, no formal submission for this study was made to the Research Committee. General measures were provided in the Rainbow clinic to ensure patient confidentiality, consent for HIV testing and support for children and guardians upon receiving a positive HIV test result.

Results

Cases and survival rates

A total of 4001 individuals started ART at MCH between July 2004 and December 2006. Children (defined as a person <15 years of age, = 473) and cases who were transferred out (= 690) were excluded from further analysis. Of 2838 cases who started ART up to 31 December 2006, 2029 (71.5%) were alive and still on ART at MCH, 376 (13.2%) were dead and 433 (15.3%) were either lost to follow-up or had stopped therapy (Table 1). The survival rates of AIDS cases fell as WHO stage advanced (85.0% in stages 1 and 2, 72.1% in stage 3 and 60.1% in stage 4). Patients with a higher BMI have better survival rates (Table 1).

Table 1.   Demographic, clinical characteristics and outcomes of 2838 adult patients infected with HIV who attended and received antiretroviral treatment at Rainbow clinic of Mzuzu Central Hospital, Malawi
VariablesAll subjectsMaleFemaleP-value
  1. Comparisons performed by chi-square tests; P value was to test the difference of survival rates between males and females. A total of 830 cases have no data of body mass index.

  2. *Means comparisons performed by Fisher’s exact test.

Number (%)28381122 (39.5)1716 (60.5) 
Age (years) at diagnosis38.6 ± 9.841.2 ± 10.036.9 ± 9.3<0.0001
Outcomes at end of period of observation, n (%)
 Alive on ART2029 (71.5)725 (64.6)1304 (76.0)<0.0001
 Died376 (13.2)188 (16.8)188 (11.0)<0.0001
 Default433 (15.3)209 (18.6)224 (13.0)<0.0001
WHO stage at start of ART, n (%)
 1 and 2 with CD4 < 200/mm3420 (14.8)155 (13.8)265 (15.4)0.232
 31832 (64.6)704 (62.8)1128 (65.7)0.104
 4586 (20.6)263 (23.4)323 (18.8)0.003
WHO stage: number (% of alive and on ART)
 1 and 2 with CD4 < 200/mm3420 (85.0)155 (75.5)265 (90.6)<0.0001
 31832 (72.1)704 (65.3)1128 (76.2)<0.0001
 4586 (60.1)263 (56.3)323 (63.2)0.091
Body mass index: number (% of alive and on ART)
 <17194 (78.2)81 (72.3)113 (83.1)0.041
 17–18.4277 (85.2)113 (83.7)164 (86.3)0.513
 18.5+1537 (88.6)524 (84.5)1013 (90.9)<0.0001
Occupation: number (% of alive and on ART)
 Business592 (80.4)220 (74.1)372 (84.1)0.003
 Farmer293 (82.3)148 (77.7)145 (86.9)0.039
 Teacher135 (87.4)47 (83.0)88 (89.8)0.257
 Student75 (72.0)36 (69.4)39 (74.4)0.797*
 Soldier/police26 (80.8)18 (77.8)8 (87.5)1.000*
 Health worker46 (91.3)12 (91.7)34 (91.2)1.000*
 Housewife635 (76.9)0 (0.0)635 (76.9) –
 Other1036 (56.9)641 (55.9)395 (58.5)0.406

Gender difference

Among these 2838 AIDS cases, females had a significantly higher survival rate than males (76.0%vs. 64.6%; P < 0.001 in Table 1). This finding persists after stratification by WHO clinical stage, BMI and occupation (Table 1). Figure 1 shows the survival analysis by Kaplan–Meier method after stratification by gender and WHO clinical stage. The log-rank test shows that female survival rates are significantly higher (P < 0.0001 for stages 1 and 2 and stage 3), but are only of borderline significance for patients in stage 4 (P = 0.076). According to the quarter when ART was started, females always showed significantly higher survival rates than males, except in July to September 2006 and October to December 2006 (data not shown).

Figure 1.

 Kaplan–Meier estimates of the survival rate between males and females stratified by WHO stage 1 and 2 (a), 3 (b) and 4 (c) according to duration of follow-up in 2838 AIDS patients. The log-rank tests revealed statistically significant differences between males and females in WHO stage 1 and 2 (a), and 3 (b) (both P values < 0.0001), but no statistically significant difference between males and females in WHO stage 4 (c) (P = 0.076).

Multivariate analysis using Cox proportional hazard model

After adjustment using Cox proportional hazard models, male gender, younger age, lower BMI and advanced WHO clinical stages were significantly associated with increased mortality (Table 2). Of these, patients in WHO stage 3 and stage 4 had the highest risk of death with HR of 2.52 (95% CI 1.56–4.39) and 5.25 (95% CI 3.18–9.27), respectively. There was a decreasing trend of HR from the younger to older age group (Table 2).

Table 2.   Hazard ratios (HR) with 95% confidence interval (CI) of mortality based on the Cox proportional hazard model of 2838 AIDS patients receiving ART at Rainbow clinic of Mzuzu Central Hospital, Malawi
VariablesHR (95% CI)P-value
Gender
 Male (reference group: female)1.70 (1.35–2.15)<0.001
Age (years)
 15–24 (reference group: >55)2.64 (1.27–5.87)0.009
 25–34 (reference group: >55)2.26 (1.23–4.64)0.007
 35–44 (reference group: >55)2.26 (1.25–4.60)0.005
 45–54 (reference group: >55)1.39 (0.73–2.94)0.328
BMI
 <17 (reference group: ≥18.5)1.52 (1.10–2.07)0.011
 17–18.5 (reference group: ≥18.5)1.09 (0.79–1.49)0.596
WHO stage
 3 (reference group: 1 and 2)2.52 (1.56–4.39)<0.001
 4 (reference group: 1 and 2)5.25 (3.18–9.27)<0.001

Discussion

The WHO clinical stage and malnutrition are well-known important prognostic factors for AIDS mortality (Calmy et al. 2006; Stringer et al. 2006), which corroborate the validity of this study (Table 2). Although the effect of gender on mortality of adult AIDS patients is not a new issue, previous studies have not shown consensus or consistent results (Melnick et al. 1994; Suligoi 1997; Farzadegan et al. 1998; Prins et al. 1999; Hogg et al. 2001; Moore et al. 2002; Napravnik et al. 2002; Garcia de la Hera et al. 2004; Nicastri et al. 2005; Calmy et al. 2006; Ferradini et al. 2006). Many of these studies have documented increased mortality in male AIDS patients (Prins et al. 1999; Hogg et al. 2001; Moore et al. 2002; Weidle et al. 2002; Garcia de la Hera et al. 2004; Nicastri et al. 2005; Calmy et al. 2006), but some studies failed to show statistically significant results, probably due to a small sample size, a short duration of follow-up (Ferradini et al. 2006) or lack of control of confounding factors such as the WHO clinical staging, nutritional condition and age. In this study from Malawi, a poor country in sub-Saharan Africa, we tried to clarify the effect of gender on mortality in patients started on ART by undertaking a more comprehensive analysis of the long-term follow-up of a cohort up to 30 months. The results confirm the relationship between male gender and mortality after controlling for confounding by other risk factors and deserve further exploration for HIV/AIDS control.

At the Rainbow clinic of MCH, more women (60.5%) than men (39.5%) receive ART. Some reasons may be explanatory of the gender difference of case numbers starting ART in Malawi. First, this reflects the gender distribution in HIV testing in the country, with more women coming for HIV testing than men (MoH Malawi 2005). As the main caretaker for children in the Malawian family, women are usually more motivated to undergo voluntary counselling and testing (VCT) and to take ART regularly. In contrast, men may be more reluctant to undergo VCT and then seek treatment, because infection with HIV still attracts stigma in Malawi. Second, the percentage is a period prevalence during 30 months. The men come for ART usually at a more advanced clinical stage and suffer from a higher mortality. So, they generally have a shorter average duration of the disease or life expectancy than women. Third, in Malawi and other developing countries in Africa, women are more likely to be underprivileged and more vulnerable to sexual exploitation. As the transmission pattern in Malawi is largely through heterosexual intercourse, there may be more women-infected HIV than men. Some orphaned girls are forced to have the commercial sex which also adds to the number of female HIV-positive clients.

After stratification by WHO clinical staging, males showed increased mortality. If further stratified by different occupations, the trend of a consistent lower survival among males persisted, except for health workers (Table 1). Females had significantly higher survival rates than males both in the occupations with a higher socioeconomic status, such as businessmen and in occupations with a lower socioeconomic status, such as farmers. Teachers, students, soldiers and police officers had the same trend, though not significant probably due to their small sample sizes. Only health workers had similar outcome rates for both males and females, probably because both are equally aware of the health impact of HIV/AIDS, the benefits of ART and would have easier access to ART than the general population. Fewer patients with an occupation default than those without. Since occupation is a good indicator for socioeconomic status, different occupations may imply different lifestyles and behaviours. The general better survival of women across different occupations indicates that the gender difference is a common factor in all societal groups.

At the Rainbow clinic, fewer women were lost to follow-up than men (13.0%vs. 18.6%, Table 1), which may be considered as an indicator of better compliance to therapy among women. In our previous study of finding the true outcomes of 126 patients lost to follow-up (defaulter) initially treated for AIDS at Rainbow clinic, there were 18 (14%) alive, 58 (46%) dead and 50 (40%) lost to follow-up. The major reasons of lost to follow-up were incorrect address (84%) and moving out (16%) (Yu et al. 2007). Among these movers, four men had moved but family remained, one man and three women had moved with their whole families. Men are more likely to migrate to other places and thus default.

This study showed a statistically significant trend of males starting on ART with more advanced clinical immunosuppression than women (Table 1), a finding reported in previous studies (Iliyasu et al. 2006; Weiser et al. 2006). This would make them more vulnerable to adverse outcomes such as death while on ART. According to our anecdotal observation and qualitative study, one of the major reasons for males to seek for medical care at a later stage and poorer compliance to ART may be related to their dignity in the Malawian culture. This result corroborates our hypothesis that males generally start ART later than females and had a worse compliance with therapy, which may lead to higher mortality (Garcia de Olalla et al. 2002; Ferradini et al. 2006; Wood et al. 2006; Wools-Kaloustian et al. 2006). Attention should be paid to unemployed men and women, who both showed relatively poor compliance.

One of the limitations of this study was the lack of data on CD4 lymphocyte count or viral load during the course of ART, which would be more suitable to serve as immunological or virological markers for adherence to therapy. However, given the life-threatening nature of AIDS, we believe that the biggest motivation of these patients for compliance is for ART, and any potential bias, if ever existed, would be minimal.

Conclusions

Gender difference was a significant factor influencing survival and mortality in adult patients on ART in both univariate and multivariate analyses in this study. Males generally sought medical care at a later clinical stage. The rates of survival and lost to follow-up of males are also worse than females across different occupations. Thus, the significantly higher mortality in male patients may be associated with their poor compliance to the ART, which may be related to the culture of masculinity. To improve the survival outcome, it is crucial to increase patients’ access for earlier treatment and to improve the compliance of patients, especially among male adults and people without definite employment, in ART scaling up programmes.

Acknowledgements

The Taiwan Medical Mission to Malawi is sponsored by the Taiwan International Cooperation and Development Fund and managed by Pingtung Christian Hospital, Taiwan. The Taiwan Medical Mission, based at MCH in the northern region of Malawi, is cooperating with Malawian staff, Ministry of Health and other organizations to fight HIV and AIDS. Professor A. D. Harries is supported by Family Health International, USA, and has an honorary position at the London School of Hygiene and Tropical Medicine. We sincerely thank for the financial support from the Department of Health of Taiwan and administrative support from the MCH and HIV unit of the Ministry of Health of Malawi. We also highly appreciate the great help from Dr Kelita Kamoto, Dr Daniel Dao-Yang Lu, Dr Wun-Yi Shao, Mr Joseph Chung-Su Wu, Ms Fu-Mei Chung and Ms Tzu-Yi Chiang for their administrative and technical support.

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