Hansmann, Andreas*†; Schim van der Loeff, Maarten F*‡; Kaye, Steve*; Awasana, Akum Aveika*; Sarge-Njie, Ramu*; O'Donovan, Diarmuid*§; Ariyoshi, Koya*∥; Alabi, Abraham*; Milligan, Paul*; Whittle, Hilton C*
In sub-Saharan Africa, 2 types of HIV are prevalent and cause disease. HIV-1 is epidemic across the continent, with 29 million Africans infected,1 but HIV-2 is mainly limited to West Africa, with an estimated 1 million people infected. In general, HIV-2 infection has been associated with substantially lower rates of transmission, disease progression, and mortality compared with HIV-1 infection.2-5
In industrialized countries, there are good data on the natural history of and survival with HIV-1 infection in men before the use of highly active antiretroviral treatment. Median survival is between 9 and 13 years depending on age at onset of infection.6
Longitudinal data on survival with HIV-1 infection in Africa are rare, and there are very few incident cohort studies. In a seroincident cohort in rural Uganda, Morgan et al7 estimated a median survival time from seroconversion of 9.8 years. A community-based seroprevalent cohort study in Malawi recently reported a median survival time of 8 years.8
Although the natural history of HIV-2 infection in African adults is less well described, studies to date indicate that the rate of disease progression is much lower than that in HIV-1 infection. In 2 community-based studies and 1 occupational cohort study from Guinea-Bissau, mortality rates were 2.3 to 6.6 times higher among HIV-2-infected adults than among uninfected adults.9-11 These rates contrast with an 11-fold higher mortality rate among HIV-1-infected compared with seronegative adults in a rural community-based study in East Africa12 and a 9-fold higher mortality in a community-based study of women in Rwanda.13
Plasma viral load (PVL) and CD4 cell count are independent predictors of mortality in HIV-1 infection in men and women,14,15 and a reduction of PVL through highly active antiretroviral treatment is strongly associated with improved survival.16-19 To our knowledge, there are no community-based studies of HIV-1 in sub-Saharan Africa that have assessed the predictive value of PVL and CD4 cell count. A community-based study of HIV-2 in Guinea-Bissau showed that PVL and CD4 cell count are clinically important independent predictors of mortality in HIV-2 infection.20
This study compares the mortality rates among HIV-1-infected, HIV-2-infected, and uninfected adult women in The Gambia and assesses the predictive value of PVL and CD4 cell percentage (CD4%) for mortality in both infections.
The women in this cohort were recruited between 1993 and 1995 during a study estimating mother-to-child transmission of HIV-1 and HIV-2 in The Gambia.4 After delivery, mothers and children were visited at 2, 6, 9, 12, 15, and 18 months by a field-worker or clinician.4,21
Between July 9, 2001, and November 1, 2001, 3 experienced, well-trained counselors/field-workers from the genitourinary clinic at the MRC in Fajara, the national referral center for HIV care, revisited all women in their homes. The counselors were blinded to the HIV status of the women. Study participants were asked for verbal informed consent, which was documented. If a woman was known to be alive but not seen at her residence, the date she was last seen alive by a close relative was recorded. If the woman was temporarily absent, she was revisited. Women who had moved within The Gambia were visited at their new address. For women who could not be traced or on whom no information could be obtained in the follow-up in 2001, the last date she was known to be alive was obtained from earlier records. Where available, data from these follow-up and clinic visits were included in our analysis. To check the quality of the collected data, 2 different field-workers visited 5.3% of the women twice in 2001.
In the initial screening during 1993-1995, all women were counseled, and only those agreeing to an HIV test were enrolled. The test results were available 2 weeks later at the same clinic from an HIV counselor for women who wanted to know their HIV status, in accordance with the National AIDS Policy.22 Very few women took advantage of this opportunity. In the follow-up in 2001, the results of the old HIV test were not provided, because the woman's serostatus might have changed in the meantime. Instead, a new test was offered to all women. The study team offered free medical treatment and fares to the next health center to any woman or other person found to be sick in the household. Women who wanted to be retested and who were found to be HIV infected were offered free care at the genitourinary clinic at MRC. HIV-1-infected women who were pregnant were offered a short course of nevirapine treatment to prevent mother-to-child transmission of HIV-1. In The Gambia, antiretroviral treatment is not yet available. The study was approved by the joint Gambian Government-MRC Ethics Committee (project number 868/825).
Serology, determination of CD4 cell count, and PVL assays were performed at recruitment as described previously.4 Briefly, screening for HIV infection was done in pools of 10, using a combined enzyme immunoassay for HIV-1 and HIV-2 (Wellcozyme HIV Recombinant; Murex Diagnostics Ltd., Dartford, UK). Individual sera from a positive pool were retested in the same assay. Those samples found to be positive were tested with the Wellcozyme HIV-1- and HIV-2-specific enzyme immunoassay (Murex Diagnostics Ltd.). Seropositivity was confirmed using a combined HIV-1 and HIV-2 peptide-based enzyme immunoassay (Pepti-LAV 1-2; Sanofi Diagnostic Pasteur SA, Marnes la Coquette, France). To determine CD4%, whole blood fluorescent antibody cell sorting (FACScan; Becton Dickinson, Oxford, UK) was used, which was adapted for field use.9 Viral loads were assayed in heparinized plasma samples stored at −80°C. RNA was extracted by the method of Boom et al,23 reverse-transcribed, and polymerase chain reaction-amplified using primers targeted to the LTR region of HIV-1 or HIV-2, and polymerase chain reaction products were quantified in a microtiter-format hybridization assay.24 The lower limit of detection of these assays was 500 copies/mL.
The data were double entered. Analysis was done with Stata version 6 (Stata Corporation, College Station, TX). Person years of observation (pyo) were calculated from the time women were enrolled until July 1, 2001, the date of death, or the last date known to be alive, whichever came first. Mortality rates were calculated as deaths per 1000 pyo, with 95% confidence intervals (CIs). Data for 10 women infected with both HIV-1 and HIV-2 were excluded from this analysis.
Time to death was examined by Kaplan-Meier graphs. Mortality rates were compared by strata of CD4% and PVL, and Mantel-Haenszel mortality rate ratios were calculated to adjust for these. Poisson regression analysis was used for multivariate analysis of mortality rates among women with HIV infection. Baseline variables that were associated with mortality in the univariate analysis (P < 0.15) were regarded as potential confounders and included in an initial model. The likelihood ratio test was used to compare the fit of models. Because mortality rates increased with increasing time from recruitment, the observation period of 8.4 years was split in 3 periods (0-2.99 years, 3-5.99 years, and 6-8.4 years), and time period was 1 of the factors adjusted for in Poisson regression analysis.
Role of the Funding Sources
The funding sources had no role in data collection, analysis, or interpretation or in the writing of the report or the decision to publish it.
The baseline characteristics of the 812 women at the time of recruitment (Table 1) show that HIV-1-positive women were younger than HIV-2-infected women (mean age: 23.4 vs. 27.0 years; t test, P < 0.001) and younger than HIV-negative women (mean age: 25.8 years; t test, P = 0.0002). HIV-1-infected women had a lower median baseline CD4% (33%) than HIV-2-infected women (42%; rank sum test, P < 0.001) and uninfected women (48%; rank sum test, P < 0.001). The median PVL, assayed for 94 HIV-1-infected women, was 13,600 copies/mL (range, 250-265,000 copies/mL). The median PVL for 228 HIV-2-infected women was 500 copies/mL (range, 250-63,000 copies/mL), which was 27-fold lower (rank sum test, P < 0.001). Comparison of PVL distributions showed 6% and 61% of HIV-1- and HIV-2-infected subjects, respectively, had PVLs of <1000 copies/mL and 9% and 0, respectively, had PVLs of >100,000 copies/mL (Fig. 1).
During the follow-up exercise between July and November 2001, of 812 women, 655 (81%) were found to be alive, 64 (8%) had died, 8 (1%) had refused further follow-up before 2001, and 85 (10%) were lost during follow-up (Table 2). The rate of loss during follow-up was 17 cases per 1000 pyo (95% CI, 14-21). The median follow-up was 6.9 years (range, 3 months to 8.4 years). No significant differences were found in HIV status, age, CD4%, PVL, or parity between women who refused or who were lost during follow-up and women with known survival status; however, those lost during follow-up had less education, were more often of the Jola ethnic group, were more often from the coastal area, and tended to have a poorer water supply (data not shown but available upon request).
For quality assurance purposes, different field-workers visited 43 women (5.3%) on 2 occasions in 2001. No discrepancies in recorded survival status occurred. There were 4 discrepancies in the date that a woman was last known to be alive (median difference, 10 months); this was caused by interviewing different informants. Despite intensive counseling by the field-workers, only 12 women opted to have a new HIV test.
Thirty-two of 101 HIV-1-infected, 23 of 243 HIV-2-infected, and 9 of 468 seronegative women died. The mortality rates were 56 deaths per 1000 pyo for HIV-1-infected (95% CI, 39-79), 16 deaths per 1000 pyo for HIV-2-infected (95% CI, 10-23), and 3.1 deaths per 1000 pyo for seronegative (95% CI, 1.6-6.0) women. Table 2 and Figure 2 compare the mortality rate and survival probability for the 3 groups (log-rank test, P < 0.0001 for all 3 pairwise comparisons). The mortality rate among women with HIV-1 infection was 18-fold higher (95% CI, 8.5-37; χ2 test, P < 0.001) than that among HIV-uninfected women. The mortality rate among women with HIV-2 infection was 5-fold higher (95% CI, 2.3-11; χ2 test, P < 0.001) than that among HIV-uninfected women and 3.6-fold lower (95% CI, 2.1-6.1; χ2 test, P < 0.001) than that among HIV-1-infected women. There were no significant differences in mortality rate by age group for HIV-1-infected (χ2 test, P = 0.6), HIV-2-infected (P = 0.11), or seronegative (P = 0.5; Table 2) women.
Among HIV-1-infected women, the mortality rate increased over time from 25 deaths per 1000 pyo (95% CI, 12-53) in the first period to 63 deaths per 1000 pyo (95% CI, 26-152) in the third period (P = 0.02), and among HIV-2-infected women, it increased from 7.5 deaths per 1000 pyo (95% CI, 3.1-18) to 34 deaths per 1000 pyo (95% CI, 17-68; P = 0.005). Among HIV-uninfected women, the mortality rate increased marginally from 2.3 deaths per 1000 pyo (95% CI, 0.74-7.1) to 4.3 deaths per 1000 pyo (95% CI, 1.1-17; P = 0.5).
Mortality by PVL and CD4%
Among HIV-1-infected study subjects, the mortality rate increased with the log of PVL, although not significantly (P = 0.09) (Table 3); among HIV-2-infected women, the mortality rate increased significantly with PVL (P = 0.002) (Table 3). When comparing the mortality rates between HIV-1- and HIV-2-infected women within the same PVL category, the rates of HIV-2 infection were lower in 2 categories and higher in 1. The Mantel-Haenszel mortality rate ratio (comparing HIV-2- with HIV-1-infected women) controlling for PVL category was 0.78 (95% CI, 0.44-1.4; P = 0.4; Table 3).
Among HIV-1-infected subjects, the mortality rate increased with decreasing CD4% (P = 0.008) (Table 3). Among HIV-2-infected women, the mortality rates also increased with decreasing CD4% (P < 0.0005). Among women with CD4% of >28%, the mortality rate was significantly lower in HIV-2-infected subjects than in HIV-1-infected subjects (χ2 test, P < 0.001), but in the 2 lower CD4% categories, there were no significant differences in mortality rates between the 2 infections (P = 0.4 each). The Mantel-Haenszel mortality rate ratio controlling for CD4% was 0.38 (95% CI, 0.22-0.67; P < 0.0005; Table 3).
The following variables were included in an initial Poisson model as potential confounders: parity, ethnic group, educational status, area of residence, serological syphilis, number of woman's live-born children who had died, circumcision status, number of people sharing the same bedroom, smoking, and whether living with the father of the last child. In the multivariate analysis, only PVL and CD4% were independent predictors of mortality. Age was a priori in the model, and time period was a confounder and kept in the model as well. After adjusting for the other variables, each 10% decrease in CD4% was associated with a 1.6-fold increase in mortality rate (95% CI, 1.1-2.3; P = 0.02) among HIV-1-infected women and a 1.5-fold increase (95% CI, 1.0-2.3; P = 0.046) among HIV-2-infected women (Table 4). After adjusting for the other variables, a 1-log increase in PVL was associated with a 1.8-fold increase in mortality rate (95% CI, 0.9-3.4; P = 0.08) for HIV-1-infected women. Because 41% of HIV-2-infected women had a PVL below the detection limit, we could not calculate the effect of a 1-log increase in PVL in HIV-2 infection. In a multivariate analysis using categories, the mortality rate was 1.3-fold (95% CI, 0.36-4.5) higher among women with PVLs between 1000 and 9999 copies/mL and 8.7-fold (95% CI, 2.8-28) higher among women with PVLs of ≥10,000 copies/mL compared with women with PVLs of <1000 copies/mL. The mortality rate among HIV-2-infected women with normal CD4% and undetectable PVL was not significantly different from that among seronegative women (P = 0.6).
In an analysis combining HIV-1 and HIV-2, each 10% decrease in CD4% was associated with a 1.7-fold increased risk of mortality (95% CI, 1.3-2.2; P < 0.0005). PVL was also associated with mortality: rate ratios were 1.8 (95% CI, 0.66-4.9) for those with PVLs between 1000 and 9999 copies/mL and 4.4 (95% CI, 1.6-12) for those with PVLs of ≥10,000 copies/mL compared with the baseline group (<1000 copies/mL). When adjusted for CD4%, PVL, age group, and time period, the mortality hazard ratio for HIV-2 compared with HIV-1 was 0.74 (95% CI, 0.36-1.5), which was not significant (P = 0.4).
To our knowledge, this is the first community-based study to compare the mortality of both HIV-1 infection and HIV-2 infection in persons from the same population, confirming that the excess mortality of HIV-2 infection is much less than that of HIV-1 infection.7,10,12
The study confirms data from other community-based studies showing that mortality rates among African HIV-1-positive patients are comparable with those among HIV-1-infected patients in industrialized countries before the introduction of highly active antiretroviral treatment.7,8 Eight years after recruitment into this seroprevalent cohort, >50% of HIV-1-infected women were still alive.
Finally, this study shows that PVL and CD4% are independent and significant predictors for mortality of HIV-2 infection in West Africa, confirming the results of an earlier community-based study in Guinea-Bissau19 and clinic-based studies in The Gambia.25,26 HIV-2-infected women with normal CD4% had a significantly lower mortality than did HIV-1-infected women with normal CD4%, but among women with low CD4%, there were no significant differences in mortality between the 2 HIV types. These findings are in agreement with findings from a clinical cohort in The Gambia.5
A possible source of selection bias is that women were pregnant when they were recruited, and fertility is reduced among HIV-infected women.27-29 Because fertility declines with duration of HIV-1 infection,28 it is likely that on average HIV-1-infected women in this study were infected relatively recently.29 Thus, they are less representative of a seroprevalent adult population cohort, and the HIV-1-associated mortality rates among populations are generally higher than those estimated in this study.30
Up to 18 months after delivery, the women were visited quarterly, and the loss to follow-up was limited. The next visit was 4-7 years later, and this long time gap and the associated loss to follow-up could be a source of bias. However, there were no significant differences in the key baseline variables (age, CD4%, PVL, and parity) between those lost to follow-up and those who were not.
We had anticipated that many women would wish to obtain their HIV status after being counseled a second time, but this did not transpire. Potential reasons for the poor uptake could be the stigma attached to the disease, lack of effective antiretroviral treatment at the time of test offering, and counseling by male field-workers. Voluntary counseling and testing are considered valuable tools in the fight against HIV and AIDS,31 but this low acceptance ratio of HIV testing suggests that the uptake may be very low in societies where HIV disease is stigmatized and effective antiretroviral therapy is unavailable.
The association between PVL and mortality in HIV-1 infection has been confirmed in various studies14 and also for women,15 but it was of borderline significance (P = 0.08) in our study. This may have been due to low power, because the number of HIV-1-infected women with available PVLs was small (94 women).
This study shows that, like in HIV-1 infection,14 PVL is a key predictor of mortality in HIV-2 infection. Although in univariate analysis the mortality of HIV-2 infection was much lower than that of HIV-1 infection, HIV type was not an independent predictor of mortality after adjusting for PVL, CD4%, age group, and time period. This suggests that the lower mortality of HIV-2 infection can be explained by the generally lower PVL and higher CD4% in HIV-2 infection,24,26 indicating a lower virulence of HIV-2.
An intriguing question remains: why do some people infected with HIV-2 develop a high PVL and rapid decay of the immune system and others do not? This is not due to subtype (all HIV-2-infected patients in The Gambia have subtype A)32 but could be due to intrasubtype variations.33 The transmission route, infecting dose, genetic factors such as HLA type, and the HLA type of the infecting partner may be important as well. Further studies to elucidate these agent, host, and environment factors are needed.
This study indicates that PVL and CD4% are of great value in predicting the outcome of infection: the mortality rate among women with a normal baseline CD4% and a baseline PVL of <500 copies/mL was not significantly different from that among seronegative women (P = 0.6). Because clinical markers alone do not reliably predict mortality,34,35 baseline CD4% or PVL measurement may be important to guide decisions to start antiretroviral treatment. Currently, there are no guidelines for treatment of HIV-2 infection. Our data suggest that the same clinical, viral load, and CD4 cell count criteria should be applied for HIV-2 infection as for HIV-1 infection when considering the use of antiretroviral treatment. Antiretroviral drugs are effective against HIV-2,36,37 with the exception of nonnucleoside reverse transcriptase inhibitors.38,39 Most HIV-2-infected people live in Africa, but unfortunately, few HIV-2-infected patients in Africa are receiving antiretroviral treatment. Cohort studies comparing the response of HIV-1- and HIV-2-infected patients to treatment are needed.
The authors thank all the women and their families who participated in the study; Alieu Jatta, Baba Danso, and Saikou Badjie (counselors/field-workers); Aji Fatou Jallow and Majulla Saidy for data entry; the divisional health teams in The Gambia; and Dr. Martin Weber (WHO, Geneva), Dr. Tumani Corrah and Professor Keith McAdam (MRC Laboratories, The Gambia), Saihou Ceesay (National AIDS Secretariat, The Gambia), Dr. Gisela Schneider (WEC International), Dr. Shabbar Jaffar and Professor Richard Hayes (LSHTM), and Professor Roel Coutinho (GG&GD, Amsterdam) for their advice and support.
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