Is HIV-2- induced AIDS different from HIV-1-associated AIDS? Data from a West African clinic
Martinez-Steele, Euridiceb; Awasana, Akum Aveikaa; Corrah, Tumania; Sabally, Saihoua; van der Sande, Mariannea; Jaye, Assana; Togun, Toyina; Sarge-Njie, Ramua; McConkey, Samuel Ja; Whittle, Hiltona; van der Loeff, Maarten F Schima,b
From the aMedical Research Council Laboratories, Fajara, The Gambia
bLondon School of Hygiene & Tropical Medicine, London, UK.
Received 29 April, 2005
Revised 23 September, 2006
Accepted 11 October, 2006
Correspondence to Dr Maarten Schim van der Loeff, Center for Poverty-related Communicable Diseases, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. E-mail: email@example.com
Background: Although AIDS is less frequent following HIV-2 than HIV-1 infection, it is unclear whether the clinical picture and clinical course of AIDS are similar in the two infections.
Objectives: To compare the pattern of AIDS-defining events, CD4 cell count at the time of AIDS diagnosis, survival from time of AIDS, and CD4 cell count near time of death in HIV-1 and HIV-2-infected patients.
Methods: Adult patients with AIDS who attended the clinics of the MRC in The Gambia were enrolled. AIDS was diagnosed according to the expanded World Health Organization case definition for AIDS surveillance (1994).
Results: Three hundred and forty-one AIDS patients with HIV-1 and 87 with HIV-2 infection were enrolled. The most common AIDS-defining events in both infections were the wasting syndrome and pulmonary tuberculosis. The median CD4 cell count at AIDS was 109 cells/μl in HIV-1 and 176 in HIV-2 (P = 0.01) and remained significantly higher in HIV-2 after adjustment for age and sex (P = 0.03). The median time to death was 6.3 months in HIV-1 and 12.6 months in HIV-2-infected patients (P = 0.03). In a multivariable analysis adjusting for age, sex and CD4 cell count, the mortality rates of HIV-1 and HIV-2-infected patients were similar (P = 0.25). The median CD4 cell count near time of death was 62 and 120 cells/μl in HIV-1 and HIV-2-infected patients, respectively (P = 0.02).
Conclusions: HIV-2 patients have a higher CD4 cell count at the time of AIDS, and a longer survival after AIDS. The mortality after an AIDS diagnosis is more influenced by CD4 cell count than HIV type.
In West Africa both HIV-1 and HIV-2 are prevalent. HIV-2 infection can cause AIDS, but the median time to AIDS is longer and only a proportion of infected patients develop AIDS . Earlier studies have shown that in the advanced stages of infection, as defined by CD4 cell count < 200 cells/μl, there is no difference in mortality between patients infected with HIV-1 and those infected with HIV-2 [2,3]. It is not entirely clear whether AIDS is different in HIV-2-infected patients compared to HIV-1-infected patients, in terms of clinical picture, CD4 cell count, prognosis, and CD4 cell count at death.
Results from an autopsy study from Cote d'Ivoire suggested a more prolonged terminal disease course in HIV-2-infected patients . We reported earlier that Kaposi's sarcoma (KS) was significantly less common among HIV-2 than among HIV-1-infected patients, in spite of similarly high human herpes virus 8 (HHV8) infection levels and after adjusting for CD4 cell counts .
There are very few studies from sub-Saharan Africa that describe the CD4 cell counts at which HIV-associated opportunistic infections occur , and it is unknown whether the CD4 cell counts at which these conditions occur differ between HIV-1 and HIV-2.
Median survival times of HIV-1-infected patients with AIDS in developing countries range from 2 to 9 months [7–14]. The median survival of HIV-2-infected patients with AIDS ranged from 5 to 8 months in three small African studies [9,10,15].
In HIV-1-infected AIDS patients in the US and Europe the CD4 cell count near the time of death is close to zero . In Africa, studies of HIV-1-infected individuals reported median counts of 61 , 88  and 90 cells/μl, respectively . Two studies of HIV-2 infection reported a median CD4 cell count of 61  and 146 cells/μl, respectively .
The objectives of this study were to make four comparisons between HIV-1 and HIV-2-infected AIDS patients: the pattern of AIDS-defining events, the CD4 cell count at the time of AIDS diagnosis, the survival from the time of AIDS diagnosis, and the CD4 cell count near the time of death. These issues are important in determining whether HAART should be started at different time points for HIV-2 compared with HIV-1-infected patients.
The study was conducted at the Genito-Urinary Medicine (GUM) clinic of the Medical Research Council (MRC) Laboratories in Fajara, The Gambia. This clinic was the national referral centre for HIV care in The Gambia during the period of this study. HIV-infected patients at this clinic were either referred from other hospitals or clinics, or were diagnosed with HIV at the MRC clinic. Frequent reasons for testing were: presence of a sexually transmitted infection (STI), being a female commercial sex worker (CSW), having tuberculosis (TB), having signs or symptoms suggestive of HIV infection, screening prior to blood donation, and being a sexual partner of an HIV or STI patient.
At every visit to the clinic a medical history and physical examination were done, and additional investigations (X-rays, microbiology, biochemistry, haematology, biopsies) if indicated. At the end of every visit (or admission) a clinical form was completed by the attending physician. A Karnofsky score  and a score on the WHO performance scale (1 to 4)  were assigned, and body weight and temperature recorded. Body mass index (BMI) was calculated by dividing the weight (in kg) by the squared height (in m) . In May 1997 the expanded WHO case definition for AIDS surveillance  was adopted. According to this case definition, AIDS is diagnosed if the patient has a positive HIV antibody test, and at least one of a list of nine conditions (see Appendix). A manual that defines the criteria for presumptive and for confirmed diagnosis of each of the conditions was adopted prior to the study (summarized in the Appendix). In practice, presumptive diagnoses were made more often than confirmed diagnoses. For the purpose of this analysis and in order to avoid over-diagnosing AIDS, we required a confirmed diagnosis for the following four conditions: cryptococcal meningitis, pulmonary tuberculosis (PTB), extrapulmonary tuberculosis (EPTB), and oesophageal candidiasis. (It proved difficult to apply a consistent approach to the diagnosis of oesophageal candidiasis over the years, and therefore a confirmed diagnosis was required for this condition). We accepted presumptive diagnoses for the following conditions: wasting syndrome, KS, neurological impairment sufficient to prevent independent daily activities, life-threatening pneumonia or a second or later episode of pneumonia, and invasive cervical carcinoma (see Appendix). The wasting syndrome was here defined as ≥ 10% body weight loss or cachexia, with diarrhoea or fever, or both, intermittent or constant, for at least 1 month, not known to be due to a condition unrelated to HIV .
If a patient had AIDS on the first visit the patient was considered to be a prevalent case. If the diagnosis was made at a second or later visit, and the interval between that visit and the previous one was less than 6 months, the patient was considered to be an incident case.
Patients were invited to attend clinic every 3 months. If patients did not return for scheduled visits, they were visited at home by field workers to assess vital status and to encourage them to attend clinic. Most patients died at home, the causes of death being unknown in those cases.
Patients aged 15 years or older who were diagnosed with AIDS between 7 May 1997 and 1 July 2003 were eligible for this study. Patients with HIV infection of undetermined type, those with HIV-1 and HIV-2 dual infection, those seen at the clinic prior to 7 May 1997, those without a CD4 cell count, those with a CD4 cell count more than 180 days from the date of AIDS diagnosis, and the few patients who were treated with antiretroviral drugs, were excluded from this analysis. For the survival analysis, only patients recruited up to 31 October 2002 were included, and the end of the observation period was 31 December 2002. For the analysis of the CD4 cell count near the time of death, only patients who had a CD4 cell count done within 3 months before death were included.
During the time of this study antiretroviral therapy was not available in The Gambia, except for 14 patients enrolled in a pilot study. From 1 July 1999 a policy of chemoprophylaxis with daily co-trimoxazole for all patients with CD4 cell counts below 500 cells/μl was in place. Patients diagnosed with tuberculosis were treated according to the national guidelines for TB treatment by the national tuberculosis control programme with four drugs during the first 2 months and rifampicine and INH for four more months. Patients with HIV-1 or HIV-2 were managed in the same way.
HIV diagnosis was based on a combination of enzyme-linked immunosorbent assay tests, as described before . Lymphocyte subsets were analysed by FACS Calibur (Becton Dickinson, Oxford, UK). CD4 cell counts were done at recruitment, and every 6 months thereafter. Plasma viral loads were not done routinely in this study.
All data were double entered and validated. The distribution of CD4 cell counts was skewed to the right; after log transformation the distribution was approximately normal. Some analyses were stratified by CD4 cell count (CD4 < 200, 200–499 and ≥ 500 cells/μl). In the analysis age was grouped into three categories (15–29, 30–39, and 40 years and above). Differences in proportions between groups were compared by chi-square test or Fisher's exact test, and differences in continuous variables by the rank-sum test. Multivariate Gaussian regression was used to compare CD4 cell counts between groups of patients.
Observation time for the survival analysis was calculated as the time from AIDS diagnosis to death, or date last seen alive, or 31 December 2002, whichever came first. Mortality rates were calculated as the number of deaths per 100 person-years of observation (pyo). Cox regression analysis was done to compare mortality hazard rates adjusting for confounding variables.
The study was approved by the Gambia Government/MRC Joint Ethics Committee and the Ethics Committee of the London School of Hygiene & Tropical Medicine. All patients gave informed consent.
Between 1 May 1997 and 1 July 2003, AIDS was diagnosed in 528 patients aged 15 years or older. Twenty-one patients who had HIV infection of undetermined type, 27 who had HIV-1 and HIV-2 dual infection, 36 who had no CD4 cell count, and 16 who had a CD4 cell count more than 6 months from the date of AIDS diagnosis were excluded. Of the remaining 428 patients, 341 (80%) had HIV-1 infection and 87 (20%) had HIV-2 infection. One hundred and forty-eight patients (35%) were considered to be incident AIDS cases, 280 (65%) prevalent AIDS cases. HIV-2 patients with AIDS were older than HIV-1 patients (Table 1). There were no significant differences between the two infections in the proportion of females or of patients who had been prescribed co-trimoxazole chemoprophylaxis prior to AIDS; the BMI at the time of AIDS was similar in the two infections.
CD4 cell count around time of AIDS
The median time difference between date of AIDS diagnosis and CD4 cell count was 1 day for both HIV-1 and HIV-2-infected patients. The median CD4 cell count around the time of the AIDS diagnosis was 109 cells/μl in HIV-1 and 176 cells/μl in HIV-2-infected patients (P = 0.01). Forty-one percent of HIV-2-infected patients had a CD4 cell count ≥ 200 cells/μl compared to only one-third of HIV-1 patients (Table 1).
In a multivariate Gaussian regression with adjustment for age and sex, the difference in the geometric mean CD4 cell count around the time of AIDS between HIV-1 and HIV-2-infected patients remained significant (126.7 versus 180.7 cells/μl, P = 0.026).
The most common AIDS-defining events were the wasting syndrome and PTB (Table 1). The pattern was very similar between HIV-1 and HIV-2-infected patients with two exceptions: the wasting syndrome was significantly more common among HIV-2-infected patients (P = 0.04), and Kaposi's sarcoma was significantly less common among HIV-2 compared to HIV-1-infected patients (3.4 versus 11.4%; P = 0.02).
The median CD4 cell count was higher in those diagnosed with invasive cervical carcinoma (419 cells/μl; P = 0.01 compared with those without the condition), EPTB (206 cells/μl; P = 0.11)), and life-threatening or second episode of pneumonia (173 cells/μl; P = 0.004), and lower in those who had wasting syndrome (84 cells/μl; P = 0.0002) or cryptococcal meningitis (38 cells/μl; P = 0.02) (Table 2).
Follow-up and mortality
Thirty patients were diagnosed with AIDS after 31 October 2002 and therefore not eligible for the survival analysis. Of the remaining 398 patients, 71 (18%) were lost to follow-up, 261 (66%) died, and 66 (17%) were alive at the end of the observation period (Table 3). There were no significant differences in the distribution of HIV type, the proportion of females, the proportion of incident AIDS cases, the median age or the median CD4 cell count at the time of AIDS between those who remained in the study and those lost to follow-up, but the latter did have a higher BMI around the time of AIDS diagnosis (18.7 versus 16.4 kg/m2; P = 0.02). The mortality rate was 87 per 100 pyo [95% confidence interval (CI), 76–100] among HIV-1 patients and 52 (95% CI, 39–69) among HIV-2-infected patients (Table 3). Figure 1 shows the survival probability of HIV-1 and HIV-2-infected patients from the time of AIDS diagnosis. The estimated median survival was 6.3 months in HIV-1 and 12.6 months in HIV-2 (log rank test; P = 0.03). Mortality rates were strongly associated with CD4 cell count at the time of AIDS diagnosis (P < 0.001), marginally associated with sex (men having a higher mortality rate then women; P = 0.08) and not with age (P = 0.5). The mortality rate of AIDS patients with CD4 cell counts below 200 cells/μl was more than four times higher than that of patients with CD4 cell counts ≥ 500 cells/μl. The crude mortality rate ratio of HIV-2-infected patients compared with HIV-1-infected patients was 0.72 (95% CI, 0.53–0.98; P = 0.03). In a Cox regression model adjusting for sex, age and CD4 cell count at time of AIDS, the mortality hazard ratio of HIV-2 versus HIV-1-infected patients was 0.83 (95% CI, 0.61–1.14; Wald test, P = 0.25).
Mortality rates differed by AIDS-defining condition, and were highest among patients with neurological impairment, cryptococcal meningitis, and wasting syndrome (181, 139 and 137 per 100 pyo, respectively) and lowest among patients with cervical cancer, life-threatening pneumonia or a second episode of pneumonia, or PTB (34, 38 and 53 per 100 pyo, respectively). Among patients with the wasting syndrome the mortality rate was significantly lower in HIV-2 compared with HIV-1 patients (90 versus 166 per 100 pyo; hazard ratio = 0.6 (95% CI, 0.4–0.9); P = 0.02); otherwise there were no significant differences in mortality rates by AIDS-defining condition between HIV-1 and HIV-2. Figure 2 shows the CD4 cell count at diagnosis of various AIDS-defining events and the median survival time from each of these conditions.
CD4 cell count near the time of death
Of the 261 patients who died, a CD4 cell count was done less than 3 months before death in 144 (115 HIV-1 and 29 HIV-2). The median time between the last CD4 cell count and the date of death was 27 days and was not significantly different between HIV-1 and HIV-2-infected patients (rank-sum test; P = 0.79). The median [interquartile range (IQR)] CD4 cell count was 62 cells/μl (IQR, 25–139) in HIV-1 and 120 cells/μl (IQR, 50–299) in HIV-2 (rank-sum test, P = 0.02). After adjusting for age and sex, the geometric mean CD4 cell count of HIV-1-infected patients near the time of death was significantly lower than that of HIV-2-infected patients (81 versus 156 cells/μl; P = 0.02).
In this West African clinic, wasting syndrome and PTB were the most frequent AIDS-defining events. This was the case for both HIV-1 and HIV-2-infected patients and this is in agreement with another study from West Africa .
In a study from Cote d'Ivoire many patients were found to have had EPTB at autopsy, but had not been diagnosed with TB while alive . In our study PTB was common and EPTB uncommon. We suspect that a large proportion of patients with the wasting syndrome in fact may have had EPTB. We are currently conducting a study in HIV patients with CD4 cell counts below 200 cells/μl, who are undergoing a more vigorous diagnostic work-up in order to establish the proportion of them in which TB can be diagnosed.
In a previous study from the same clinic, but covering an earlier period, we found that KS was less common among HIV-2 patients ; the same was the case in this analysis. This does support the hypothesis that there is a direct interaction between the causative virus of KS, HHV8, and HIV-1 specifically .
CD4 cell count at time of AIDS
The median CD4 cell count at the time of a clinical AIDS diagnosis was 109 cells/μl in HIV-1-infected patients. This is similar to the median CD4 cell counts observed by earlier studies in sub-Saharan Africa (medians ranging from 57 to 296 cells/μl) [9,11,12,27]. The median CD4 cell count among HIV-2 patients with AIDS was 176 cells/μl; this falls within the range of median values of 73 to 358 cells/μl reported by other studies [9,25,27–29]. The CD4 cell count at AIDS was higher in the HIV-2 patients, and after adjusting for age and sex this difference remained significant (P = 0.026). We conclude that in our clinic population AIDS occurs at higher CD4 cell counts among HIV-2 patients compared with HIV-1 patients. This difference is largely responsible for the observed better survival of HIV-2-infected AIDS patients.
The nine AIDS-defining conditions occurred at different CD4 cell counts, with cryptococcal meningitis and wasting syndrome occurring at low and cervical cancer and EPTB at higher CD4 cell counts. The median CD4 cell counts at which these conditions occurred were all higher than the values usually seen in the USA and Europe, except for TB . There are few clinic-based studies in Africa with comparable data.
Survival after a clinical AIDS diagnosis
The prognosis after an AIDS diagnosis was very poor; the median survival was less than 7 months. The survival was longer in HIV-2-infected patients than in HIV-1-infected patients (12.6 versus 6.3 months). However in both infections the CD4 cell count at the time of the clinical AIDS diagnosis was the most important determinant of survival. When adjusted for age, sex, and CD4 cell count, the mortality rates of HIV-2 and HIV-1-infected patients were not significantly different. The CD4 cell count has been recognized as a crucial determinant of survival both in HIV-1  and in HIV-2 [2,3,9,32]. Thus, when deciding about antiretroviral treatment, the CD4 cell count (or the symptomatology) should dictate when to start, not the HIV-type. The choice of the drug regimen will depend on the HIV type, as HIV-2 is not sensitive to non-nucleoside reverse transcriptase inhibitors [33,34].
CD4 cell count near time of death
In this clinic population the median CD4 cell count near the time of death was 62 cells/μl in HIV-1-infected patients, which was similar to the median counts of 61, 88 and 90 cells/μl was reported by others [4,11,17]. The median CD4 cell count in HIV-2 patients was 120 cells/μl, which was between two earlier reported median values of 61 and 146 cells/μl [4,18]. The CD4 cell count near the time of death was 58 cells/μl higher in HIV-2 patients than in HIV-1 patients, and this difference was significant. This finding does not support earlier suggestions that HIV-2 patients have a slower progression in the later stages of disease and die at lower CD4 cell counts [4,35].
Limitations of the study
As HIV-2 patients have higher CD4 cell counts at registration at our clinic than HIV-1 patients [2,36], this might have biased upwards the estimate of the median CD4 cell count in HIV-2 patients with AIDS. An analysis limited to incident AIDS cases, stratified by baseline CD4 cell count (i.e. CD4 cell count at HIV diagnosis, prior to AIDS), could have addressed this, but the number of incident cases was too low for this.
The loss to follow-up was 18%, and was not different by HIV type. Those lost to follow-up had a significantly higher BMI and tended to have higher CD4 cell counts; this may have caused some overestimation of the mortality rates. There are no reasons to assume that this effect differed by HIV type, so this should not affect the survival analysis.
In conclusion, this study confirmed that there are no major differences in clinical AIDS presentation between HIV-1 and HIV-2-infected patients, apart from a higher frequency of wasting syndrome and a lower frequency of KS in HIV-2 patients. In this setting, HIV-2-infected AIDS patients had higher CD4 cell counts at diagnosis and consequently a lower mortality rate than HIV-1-infected patients. HIV-2 patients had higher CD4 cell counts at death than HIV-1 patients.
In this study we used the expanded WHO case definition for AIDS surveillance, which is based on a positive antibody test and the presence of one or more AIDS-defining conditions. Forty-one percent of the HIV-2-infected patients and 32% of the HIV-1-infected patients with AIDS did have CD4 cell counts above 200 cells/μl. This suggests that AIDS occurs at higher CD4 cell counts in Africa than in US and Europe.
Even among AIDS patients with a CD4 cell count ≥ 500 cells/μl the mortality rate was very high, in both HIV-1 and HIV-2-infected patients (22 and 27 per 100 pyo, respectively). This justifies using the expanded WHO case definition as a starting point for HAART.
We thank all patients who participated in the study. We also thank the field workers, nurses, data entry staff, and laboratory assistants for their hard work and dedication. We thank Rachel Bennett and Mary Dowling for data extraction, and Linda Morison, Alison Grant and Katherine Fielding, for useful discussions. We acknowledge the continuing support of Saihou Ceesay (Director of the National AIDS Secretariat).
Sponsorship: This study was funded by the Medical Research Council (UK).
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AIDS-defining conditions, according to the expanded WHO case definition for AIDS surveillance (WHO 1994), and diagnostic criteria
‘For the purposes of AIDS surveillance an adult or adolescent (> 12 years of age) is considered to have AIDS if a test for HIV antibody gives a positive result and one or more of the following conditions are present.’
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