The relationship between CD4+ T-cell counts determined soon after seroconversion with HIV-1 (baseline CD4), nadir CD4, and CD4 levels attained during highly active antiretroviral therapy (HAART) is unknown.
Longitudinal, including baseline (at or soon after HIV diagnosis), intermediate (nadir), and distal (post-HAART) CD4+ T-cell counts were assessed in 1085 seroconverting subjects who achieved viral load suppression from a large well-characterized cohort. The association of baseline with post-HAART CD4+ T-cell count was determined after adjustment for other relevant covariates.
A higher baseline CD4+ T-cell count predicted a greater post- HAART CD4+ T-cell count, independent of the nadir and other explanatory variables. Together, baseline and nadir strongly predicted the post-HAART CD4+ count such that a high baseline and lower nadir were associated with a maximal immune recovery after HAART. Likelihood of recovery of the baseline count after HAART was significantly higher when the nadir/baseline count ratio was consistently ≥0.6.
Among viral load suppressing seroconverters, the absolute CD4+ T-cell count attained post-HAART is highly dependent on both baseline and nadir CD4+ T-cell counts. These associations further support the early diagnosis and initiation of HAART among HIV-infected persons.
CD4 count; highly active antiretroviral therapy; outcomes; predictors; treatment response
Despite suppression of the human immunodeficiency virus type 1(HIV-1) load by highly active antiretroviral therapy (HAART), recovery of CD4+ T cell counts can be impaired. We investigated whether this impairment may be associated with hyporesponsiveness of T cells to γ-chain (γc) cytokines known to influence T cell homeostasis.
The responsiveness of T cells to interleukin (IL)-2, IL-7, and IL-15 was determined by assessing cytokine-induced phosphorylation of the signal transducer and activator of transcription 5 (STAT5) in peripheral T cells obtained from 118 HIV-positive subjects and 13 HIV-negative subjects.
The responsiveness of T cells to interleukin (IL)-7 but not to IL-2 or IL-15 was lower among HIV-positive subjects than among HIV-negative subjects. Among subjects with viral load suppression, the degree of IL-7 responsiveness (1) correlated with naive CD4+ T cell counts and was a better immune correlate of the prevailing CD4+ T cell count than were levels of human leukocyte antigen-DR1 or programmed death-1, which are predictors of T cell homeostasis during HIV infection; and (2) was greater in subjects with complete (i.e., attainment of ≥500 CD4+ T cells/mm3 ≥5 years after initiation of HAART) versus incomplete immunologic responses. The correlation between plasma levels of IL-7 and CD4+ T cell counts during HAART was maximal in subjects with increased IL-7 responsiveness.
Responsiveness of T cells to IL-7 is associated with higher CD4+ T cell counts during HAART and thus may be a determinant of the extent of immune reconstitution.
The in vivo impact of mannose-binding lectin (MBL), a molecule involved in innate immunity, on the pathogenesis of human immunodeficiency virus (HIV)–1 infection and AIDS is unknown.
A total of 1102 HIV-positive and 2213 HIV-negative adult subjects were screened for polymorphisms in the coding and promoter regions of MBL2, the gene that encodes MBL.
Variations in MBL2 did not influence the risk of acquiring HIV-1. Heterozygosity for coding mutations (O allele) and homozygosity for the −221 promoter polymorphism (X allele) in MBL2 were associated with a delay in and an accelerated rate of disease progression, respectively. MBL2 variations influenced the rate of progression to AIDS-defining illnesses. In a multivariate model, the effects of MBL2 variations were independent of several parameters known to influence disease progression, including steady-state viral load, baseline CD4+ T cell counts, and delayed-type hypersensitivity skin test responses, an in vivo marker of cell-mediated immunity. The effects of MBL2 variations were most evident in those who possessed protective genotypes of CCR5 and a high copy number of CCL3L1, the most potent HIV-suppressive CCR5 ligand.
MBL2 genotypes are independent determinants of HIV disease progression and heterozygosity for MBL2 coding mutations confer disease-retarding effects. MBL-dependent immune responses may play a role in the pathogenesis of HIV infection.
Persons infected with human immunodeficiency virus (HIV) have a high prevalence of insomnia (46%) and daytime drowsiness (30%). Factors associated with insomnia among patients with HIV infection include depression and increased waist size. Screening for sleep disturbances should be considered among HIV-infected persons.
Background. Sleep disturbances are reportedly common among persons infected with human immunodeficiency virus (HIV), but recent data, including comparisons with HIV-uninfected persons, are limited.
Methods. We performed a cross-sectional study among early-treated HIV-infected military beneficiaries (n = 193) to determine the prevalence and factors associated with insomnia (Pittsburgh Sleep Quality Index [PSQI]) and daytime sleepiness (Epworth Sleepiness Scale [ESS]). Data were compared with HIV-uninfected persons (n = 50) matched by age, sex, race or ethnicity, and military rank.
Results. Forty-six percent of HIV-infected persons had insomnia (PSQI >5), and 30% reported daytime drowsiness (ESS ≥10). The prevalence of insomnia and daytime sleepiness was not significantly higher compared with the HIV-uninfected group (38% [P = .30] and 20% [P = .18], respectively). In the multivariate model, factors associated with insomnia among HIV infected patients included depression (odds ratio [OR], 16.8; 95% confidence interval [CI], 2.0–142.1; P = .01), increased waist size (OR, 2.7; 95% CI, 1.4–5.1; P = .002), and fewer years of education (OR, 0.8; 95% CI, .7–.95; P = .006). Neurocognitive impairment (diagnosed in 19% of HIV-infected participants) was not associated with insomnia; however, HIV-infected persons with insomnia were 3.1-fold more likely to have a decline in activities of daily living than those without insomnia (23% vs 9%; P = .01). Only 18% of HIV-infected persons reported using a sleep medication at least weekly.
Conclusions. HIV-infected persons have a high prevalence of insomnia, but among an early-treated cohort this rate was not significantly higher compared with HIV-uninfected persons. Factors associated with insomnia among HIV-infected patients include depression and increased waist size. Prompt diagnosis and treatment of sleep disturbances are advocated and may improve quality of life.
(See the editorial commentary by Peters and Marston, on pages 166–8.)
Background. Understanding the impact of hepatitis B virus (HBV) in human immunodeficiency virus (HIV) coinfection has been limited by heterogeneity of HIV disease. We evaluated HBV coinfection and HIV-related disease progression in a cohort of HIV seroconverters.
Methods. Participants with HIV diagnosis seroconversion window of ≤3 years and serologically confirmed HBV infection (HB) status were classified at baseline into 4 HB groups. The risk of clinical AIDS/death in HIV seroconverters was calculated by HB status.
Results. Of 2352 HIV seroconverters, 474 (20%) had resolved HB, 82 (3%) had isolated total antibody to hepatitis B core antigen (HBcAb), and 64 (3%) had chronic HB. Unadjusted rates (95% confidence intervals [CIs]) of clinical AIDS/death for the HB-negative, resolved HB, isolated HBcAb, and chronic HB groups were 2.43 (2.15–2.71); 3.27 (2.71–3.84); 3.75 (2.25–5.25); and 5.41 (3.41–7.42), respectively. The multivariable risk of clinical AIDS/death was significantly higher in the chronic HB group compared to the HB-negative group (hazard ratio [HR], 1.80; 95% CI, 1.20–2.69); while the HRs were increased but nonsignificant for those with resolved HB (HR, 1.17; 95% CI, .94–1.46) and isolated HBcAb (HR, 1.14; 95% CI, .75–1.75).
Conclusions. HBV coinfection has a significant impact on HIV outcomes. The hazard for an AIDS or death event is almost double for those with chronic HB compared, with HIV-monoinfected persons.
To evaluate whether elevated CD8 counts are associated with increased risk of virologic treatment failure in HIV-infected individuals.
Retrospective cohort study.
U.S. Military HIV Natural History Study participants who initiated HAART in 1996-2008, had 6- and 12-month post-HAART HIV RNA <400 c/ml, ≥2 subsequent HIV viral loads and a baseline CD8 count were eligible (n=817). Baseline was 12 months after HAART start, virologic failure was defined as confirmed HIV RNA ≥400 c/ml, and CD8 counts ≥1200 cells/mm3 were considered elevated. Cox models were used to examine the effect of baseline and time-updated CD8 counts on virologic failure.
There were 216 failures for a rate of 5.6 per 100 person-years (95% confidence interval [CI] 4.9-6.4). Among those initiating HAART in 2000-2008, participants with elevated baseline CD8 counts had significantly greater risk of virologic failure compared to those with baseline CD8 counts ≤600 cells/mm3 (hazard ratio [HR] = 2.68, 95% CI 1.13 – 6.35). Participants with elevated CD8 counts at >20% of prior 6-month follow-up visits had greater risk of failure at the current visit than those who did not (HR = 1.53, 95% CI 1.14 - 2.06). Those with CD8 counts that increased after HAART start had greater risk of failure than those with CD8 counts that decreased or remained the same (HR = 1.59, 95% CI 1.19 – 2.13).
Initial or serial elevated CD8 counts while on HAART or an increase in CD8 counts from HAART initiation may be early warnings for future treatment failure.
Human immunodeficiency virus; CD8 count; antiretroviral therapy; HIV viral load suppression; HIV virologic failure
Background. Vaccination provides long-term immunity to hepatitis A virus (HAV) among the general population, but there are no such data regarding vaccine durability among human immunodeficiency virus (HIV)–infected adults.
Methods. We retrospectively studied HIV-infected adults who had received 2 doses of HAV vaccine. We analyzed blood specimens taken at 1 year, 3 years, and, when available, 6–10 years postvaccination. HAV immunoglobulin G (IgG) values of ≥10 mIU/mL were considered seropositive.
Results. We evaluated specimens from 130 HIV-infected adults with a median age of 35 years and a median CD4 cell count of 461 cells/mm3 at or before time of vaccination. Of these, 49% had an HIV RNA load <1000 copies/mL. Initial vaccine responses were achieved in 89% of HIV-infected adults (95% confidence interval [CI], 83%–94%), compared with 100% (95% CI, 99%–100%) of historical HIV-uninfected adults. Among initial HIV-infected responders with available specimens, 90% (104 of 116; 95% CI, 83%–95%) remained seropositive at 3 years and 85% (63 of 74; 95% CI, 75%–92%) at 6–10 years. Geometric mean concentrations (GMCs) among HIV-infected adults were 154, 111, and 64 mIU/mL at 1, 3, and 6–10 years, respectively, compared with 1734, 687, and 684 mIU/mL among HIV-uninfected persons. Higher GMCs over time among HIV-infected adults were associated with lower log10 HIV RNA levels (β = −.12, P = .04).
Conclusions. Most adults with well-controlled HIV infections had durable seropositive responses up to 6–10 years after HAV vaccination. Suppressed HIV RNA levels are associated with durable HAV responses.
To determine whether hepatitis E virus (HEV) is a cause of hepatitis among HIV-infected persons, we evaluated 1985–2009 data for US military beneficiaries. Evidence of acute or prior HEV infection was detected for 7 (4%) and 5 (3%) of 194 HIV-infected persons, respectively. HEV might be a cause of acute hepatitis among HIV-infected persons.
Hepatitis E virus; HIV; epidemiology; hepatitis; military; viruses
To assess associations between the timing of hepatitis B virus (HBV) immunization relative to human immunodeficiency virus (HIV) diagnosis and vaccine effectiveness, US Military HIV Natural History Study cohort participants without HBV infection at the time of HIV diagnosis were grouped by vaccination status, retrospectively followed from HIV diagnosis for incident HBV infection, and compared using Cox proportional hazards models. A positive vaccine response was defined as hepatitis B surface antibody level ≥10 IU/L. Of 1,877 participants enrolled between 1989 and 2008, 441 (23%) were vaccinated prior to HIV diagnosis. Eighty percent of those who received vaccine doses only before HIV diagnosis had a positive vaccine response, compared with 66% of those who received doses both before and after HIV and 41% of those who received doses only after HIV (P < 0.01 for both compared with persons vaccinated before HIV only). Compared with the unvaccinated, persons vaccinated only before HIV had reduced risk of HBV infection after HIV diagnosis (hazard ratio = 0.38, 95% confidence interval: 0.20, 0.75). No reduction in HBV infection risk was observed for other vaccination groups. These data suggest that completion of the vaccine series prior to HIV infection may be the optimal strategy for preventing this significant comorbid infection in HIV-infected persons.
hepatitis B vaccines; hepatitis B virus; HIV; immunization; vaccination
The HIV Resistance Response Database Initiative (RDI), which comprises a small research team in the United Kingdom and collaborating clinical centers in more than 15 countries, has used antiretroviral treatment and response data from thousands of patients around the world to develop computational models that are highly predictive of virologic response. The potential utility of such models as a tool for assisting treatment selection was assessed in two clinical pilot studies: a prospective study in Canada and Italy, which was terminated early because of the availability of new drugs not covered by the system, and a retrospective study in the United States. For these studies, a Web-based user interface was constructed to provide access to the models. Participating physicians entered baseline data for cases of treatment failure and then registered their treatment intention. They then received a report listing the five alternative regimens that the models predicted would be most effective plus their own selection, ranked in order of predicted virologic response. The physicians then entered their final treatment decision. Twenty-three physicians entered 114 cases (75 unique cases with 39 entered twice by different physicians). Overall, 33% of treatment decisions were changed following review of the report. The final treatment decisions and the best of the RDI alternatives were predicted to produce greater virologic responses and involve fewer drugs than the original selections. Most physicians found the system easy to use and understand. All but one indicated they would use the system if it were available, particularly for highly treatment-experienced cases with challenging resistance profiles. Despite limitations, the first clinical evaluation of this approach by physicians with substantial HIV-experience suggests that it has the potential to deliver clinical and economic benefits.
Kaposi’s sarcoma-associated herpesvirus (KSHV) seropositivity and lytic antibody titer are predictors for Kaposi’s sarcoma (KS).
We examined demographic, viral and immunological factors that influence KSHV latent and lytic antibodies in HIV-infected patients.
Detection rate of KSHV latent but not lytic antibodies was lower in patients with CD4 cells/mm3 ≤200 than >200 (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.11–0.61) and CD8 cells/mm3 ≤400 than >400 (OR, 0.26; 95% CI, 0.07–0.67). Overall seropositivity rate was higher in patients with CD4 cells/mm3 ≤200 than >200 (OR, 2.34; 95% CI, 1.37–4.02) and HIV copies/mL >400 than ≤400 (OR, 1.70; 95% CI, 1.09–2.65). Lytic antibody level was inversely correlated with CD4 count (P<0.001). Lytic seropositivity (OR, 2.47; 95% CI, 1.35–4.50) and antibody level (adjusted difference mean optical density [admOD], 0.324; 95% CI, 0.16–0.46) were higher in patients with HIV infection >15 than ≤15 years. Hispanics had higher lytic seropositivity rate (OR, 1.71; 95% CI, 1.07–2.73) and antibody level (admOD, 0.111; 95% CI, 0.03–0.18) than non-Hispanics.
Lower CD4 and CD8 counts impair antibody response to KSHV latent antigens. Immune deterioration, long-term HIV infection and Hispanic status are risk factors for KS predictors.
KSHV; Kaposi’s sarcoma; Latent and lytic antibodies; Risk factors; HIV/AIDS
Prior studies have shown that weight may impact immune cell counts. However, few data exist about the relationship of weight and immune cell counts among HIV-infected patients. We examined documented HIV seroconverters (mean window, 15.7 months) in a prospective U.S. Military HIV Natural History Study (1 January 1986 to 20 January 2010). We estimated the association of the time-updated body mass index (BMI) category with changes in immune cell counts from HIV diagnosis across time (mean follow-up of 5.1 years) using multiply adjusted longitudinal linear mixed-effects models. Of 1,097 HIV seroconverters, 448 (41%) were overweight and 93 (8%) were obese at HIV diagnosis. Immune cell counts at HIV diagnosis did not significantly differ by BMI category. In the longitudinal models for those diagnosed before the advent of the highly active antiretroviral therapy (HAART) era, mean postdiagnosis decreases in the white cell count, total lymphocyte count, CD4 count, CD4 percentage, and CD4/CD8 ratio were less as the BMI category increased (all with P values of <0.05). Among HIV seroconverters diagnosed in the HAART era, obese compared to normal-weight patients had significantly smaller increases in CD4 counts, CD4 percentages, and the CD4/CD8 ratio (all with P values of <0.05). Similar findings were also noted among underweight versus normal-weight patients. In conclusion, although BMI was not associated with immune cell levels at the time of HIV diagnosis, weight appears to affect immune cells counts over the course of infection. In the HAART era, being either underweight or obese was associated with smaller increases in several important immune cell levels, including the CD4/CD8 ratio.
We evaluated longitudinal rates of Kaposi sarcoma (KS) and trends in CD4 counts at the time of KS diagnosis during the HIV epidemic (1985–2008). Although rates of KS have decreased, cases are now occurring at higher CD4 counts over time, with more than a third of cases diagnosed in 2002–2008 occurring at CD4 counts ≥350 cells/mm3. These data support future studies evaluating the impact of HAART initiation at higher CD4 counts to further reduce KS.
The risk of pneumococcal disease persists and antibody responses to revaccination with the 23-valent polysaccharide vaccine (PPV) are low among HIV-infected adults. We determined whether revaccination with the 7-valent pneumococcal conjugate vaccine (PCV) would enhance these responses.
In a randomized clinical trial, we compared the immunogenicity of revaccination with PCV (n=131) or PPV (n=73) among HIV-infected adults (median CD4 count 533 cells/mm3) vaccinated with PPV 3–8 years earlier. HIV-uninfected adults (n=25) without prior pneumococcal vaccination received one dose of PCV. A positive response was defined as a ≥2-fold rise (baseline to day 60) in capsule-specific IgG with a post-vaccination level value ≥1000 ng/ml for at least 2 of the 4 serotypes.
HIV-infected persons demonstrated a higher frequency of positive antibody responses to PCV vs. PPV (57% vs. 36%, p=0.004) and greater IgG concentration mean changes from baseline to day 60 for serotypes 4, 9V, and 19F (all p<0.05), but not for serotype 14. However by day 180 both outcomes were similar. Responses to PCV were greater in frequency and magnitude for all serotypes in HIV-uninfected compared with those in HIV-infected adults.
Among persons with HIV infection, revaccination with PCV was only transiently more immunogenic than PPV, and responses were inferior to those in HIV-uninfected subjects with primary vaccination. Pneumococcal vaccines with more robust and sustained immunogenicity are needed for HIV-infected adults.
HIV; epidemiology; progression; CD4 counts
To evaluate the incidence rates of anal cancer over the HIV epidemic and assess the impact of HAART use on anal cancer events.
We evaluated the incidence of and factors associated with anal cancer using longitudinal data from the prospective U.S. Natural History Study (1985-2008). Poisson regression and Cox proportional hazard models were utilized.
Among 4,506 HIV-infected males with 37,806 person-years (PY) of follow-up, anal cancer rates (per 100,000 PY) increased 5-fold, from 11 in the pre-HAART to 55 in the HAART era, p=0.02. Rates continued to increase, reaching 128 in 2006-2008. Persons with HIV infection for >15 years had a 12-fold higher rate than those with <5 years (348 vs. 28, p<0.01). At cancer diagnosis (n=19), median age was 42 years, median CD4 count was 432 cells/mm3, 74% had a CD4 nadir <200 cells/mm3, 42% had a prior AIDS event, and 74% had received HAART. From separate models, prior AIDS event (HR 3.88, p=0.01) and lower CD4 nadir (HR 0.85 per 50 cell, p=0.03) were associated with anal cancer, with a trend for a history of gonorrhea (HR 2.43, p=0.07). Duration of HAART use was not associated with a reduced risk of anal cancer (HR 0.94, p=0.42).
Incidence rates of anal cancer have progressively increased during the HIV epidemic. Persons with a longer duration of HIV infection have a substantially higher rate of anal cancer. Since HIV-infected persons are experiencing longer life expectancies and HAART does not appear protective of anal cancer, studies on preventive strategies are needed.
HIV; anal cancer; incidence rates; antiretroviral therapy; HAART; epidemiology
To assess the effect of obesity on CD4 counts, we estimated the association of time-updated BMI categories with CD4 changes among 1,001 documented HIV seroconverters. During the pre-HAART era, a higher BMI was associated with less reduction in CD4 counts over time. However during the HAART era, obese versus normal weight patients had smaller increases in CD4 counts (+69 v. +116 cells, p=0.01). Lower CD4 counts may now be another adverse consequence of obesity.
HIV; immunology; obesity; CD4 counts; antiretroviral therapy
The epidemiologic trends of hepatitis B virus (HBV) infection in HIV-infected patients over the last twenty years are largely unknown.
Prevalence and risk factors for HBV infection overall, at the time of HIV infection, and following HIV infection were examined in an ongoing observational HIV cohort study. Risk factors for HBV infection at the time of HIV diagnosis were evaluated using logistic regression, and risk for incident HBV infection following HIV diagnosis was evaluated using Cox proportional hazards models.
Of the 2769 evaluable participants, 1078 (39%) had HBV infection, of which 117 (11%) had chronic HBV. The yearly cross-sectional prevalence of HBV infection decreased from a peak of 49% in 1995 to 36% in 2008 (p<0.001). HBV prevalence at the time of HIV diagnosis decreased between 1989 and 2008 from 34% to 9% (p<0.001). The incidence of HBV infection following HIV diagnosis decreased from 4.0/100 person-years in the pre-HAART era to 1.1/100 person-years in the HAART era (p<0.001), but has remained unchanged from 2000 through 2008 (p=0.49), with over 20% of incident HBV infections having chronic HBV. Decreased risk of HBV infection following HIV diagnosis was associated with higher CD4 cell counts and the use of HBV-active HAART. Receipt of ≥1 dose of HBV vaccine was not associated with reduced risk of HBV infection after HIV diagnosis.
While the burden of HBV infection overall is slowly decreasing among HIV-infected individuals, the persistent rate of HBV infection following HIV diagnosis raises concern that more effective prevention strategies may be needed to significantly reduce HBV infections in this patient population.
Hepatitis B Virus; Human Immunodeficiency Virus; Sexually Transmitted Infections; Highly Active Antiretroviral Therapy; Hepatitis B Vaccine
As life expectancy of HIV-infected persons increases, cancers have become an important cause of morbidity and mortality. Although cutaneous neoplasms are the most common malignancies in the general population, little data exist among HIV-positive persons especially regarding the impact of HIV-specific factors.
We evaluated the incidence rates and factors associated with the development of cutaneous malignancies among HIV-infected persons by examining prospectively collected data from a large HIV Natural History Study composed of 4,490 persons (1986 to 2006). Poisson regression and Cox proportional hazards models were performed.
Six percent (n=254) of HIV-infected persons developed a cutaneous malignancy during 33,760 person-years of follow-up (mean 7.5 years). Since the advent of highly active antiretroviral therapy (HAART), incidence rates of cutaneous non-AIDS defining cancers (NADCs), in particular basal cell carcinoma, have exceeded rates of cutaneous AIDS-defining cancers such as Kaposi’s sarcoma. Factors associated with the development of cutaneous NADCs in the multivariate models included increasing age (hazard ratio (HR) 2.1; 95% CI 1.7–2.6) and race. Compared to white/non-Hispanic race, African Americans (HR 0.03, 95% CI 0.01–0.14) and other races (HR 0.14, 95% CI 0.03, 0.57) had a lower risk of cutaneous NADCs. There were no significant associations between cutaneous NADCs and time-updated CD4 counts, HIV RNA levels, or HAART receipt.
NADCs are now the most common cutaneous malignancies among HIV-infected persons. Cutaneous NADCs do not appear to be significantly associated with immune function or HAART, but rather are related to traditional factors, such as aging and skin color.
Cutaneous malignancy; skin cancer; neoplasm; HIV; basal cell carcinoma; melanoma; epidemiology; HAART
Whether HIV seroconverters are presenting with lower CD4 counts over the HIV epidemic is controversial. Additional data on whether HIV may have become more virulent on a population level, as measured by post-seroconversion CD4 counts, may provide important insights regarding HIV pathogenesis.
To determine if the post-seroconversion CD4 counts have changed over calendar time, we evaluated 2,174 HIV seroconverters as part of a large cohort study (1985-2007). Participants were documented HIV seroconverters who were antiretroviral naïve and had a CD4 count within six months of HIV diagnosis. Multiple linear regression models were used to assess trends in initial CD4 counts.
The mean initial CD4 count decreased during the study period: 632 cells/mm3 in 1985-1990, 553 cells/mm3 in 1991-1995, 493 cells/mm3 in 1996-2001, and 514 cells/mm3 in 2002-2007. During the time periods, the percentage of seroconverters with an initial CD4 count of <350 cells/mm3 was 12%, 21%, 26%, and 25%, respectively. In the multiple linear model, the mean CD4 count in 1991-1995 was -65 cells/mm3 (p<0.0001), 1996-2001 was -107 cells/mm3 (p<0.0001), and 2002-2007 was -102 cells/mm3 (p<0.0001) compared to 1985-1990. Similar trends occurred in the CD4 percentage and total lymphocyte count. African-Americans and Whites had similar decreases in initial CD4 counts during the epidemic.
A significant decline in initial CD4 counts among U.S. HIV seroconverters occurred during the epidemic. These data provide an important clinical correlate to studies suggesting that HIV may have adapted to the host resulting in a more virulent infection.
HIV; CD4 cell counts; seroconverters; virulence; military
To describe trends in incidence rates of AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs) during the HIV epidemic and to evaluate predictors, including the impact of antiretroviral therapy, of cancer development.
Retrospective analysis of a multicenter, prospective natural history study including 4,498 HIV-infected U.S. military beneficiaries with 33,486 person-years of follow-up.
Predictors evaluated included demographics, clinical data, time-updated CD4 cell counts, HIV viral loads, and antiretroviral history. Time periods were classified as early pre- (1984-1990), late pre- (1991-1995), early post- (1996-2000), and late post-(2001-2006) HAART eras. Cox proportional hazard models were used to evaluate the association of specific factors with cancer.
Ten percent of HIV-infected persons developed cancer. ADC rates increased between the early and late pre-HAART eras (7.6 and 14.2 cases per 1000 person years) and have since declined from 5.4 to 2.7 in the early and late HAART eras, respectively (p<0.001). Rates of NADCs have risen over the four time periods (2.9, 2.8, 4.2, 6.7, p=0.0004). During the late HAART era, 71% of cancers were NADCs. Predictors for ADCs included low CD4 cell count, non-cancer AIDS diagnosis, and lack of HAART. NADCs were predicted by increasing age, Caucasian race (due to skin cancers), and lack of HAART.
Although the rate of ADCs continues to fall, the rate of NADCs is rising and now accounts for the majority of cancers in HIV-infected persons. The development of NADCs is associated with increasing age among HIV patients. HAART is protective for both ADCs and NADCs.
Cancer; malignancy; HIV; military; epidemiology; HAART
The basis for the extensive variability seen in the reconstitution of CD4+ T cell counts in HIV-infected individuals receiving highly active antiretroviral therapy (HAART) is not fully known. Here, we show that variations in CCL3L1 gene dose and CCR5 genotype, but not major histocompatibility complex HLA alleles, influence immune reconstitution, especially when HAART is initiated at <350 CD4+ T cells/mm3. The CCL3L1-CCR5 genotypes favoring CD4+ T cell recovery are similar to those that blunted CD4+ T cell depletion during the time before HAART became available (pre-HAART era), suggesting that a common CCL3L1-CCR5 genetic pathway regulates the balance between pathogenic and reparative processes from early in the disease course. Hence, CCL3L1-CCR5 variations influence HIV pathogenesis even in the presence of HAART and, therefore, may prospectively identify subjects in whom earlier initiation of therapy is more likely to mitigate immunologic failure despite viral suppression by HAART. Furthermore, as reconstitution of CD4+ cells during HAART is more sensitive to CCL3L1 dose than to CCR5 genotypes, CCL3L1 analogs might be efficacious in supporting immunological reconstitution.
Polymorphisms in CCR5, the major coreceptor for HIV, and CCL3L1, a potent CCR5 ligand and HIV-suppressive chemokine, are determinants of HIV-AIDS susceptibility. Here, we mathematically modeled the potential impact of these genetic factors on the epidemic spread of HIV, as well as on its prevention.
Methods and Results
Ro, the basic reproductive number, is a fundamental concept in explaining the emergence and persistence of epidemics. By modeling sexual transmission among HIV+/HIV− partner pairs, we find that Ro estimates, and concordantly, the temporal and spatial patterns of HIV outgrowth are highly dependent on the infecting partners' CCL3L1-CCR5 genotype. Ro was least and highest when the infected partner possessed protective and detrimental CCL3L1-CCR5 genotypes, respectively. The modeling data indicate that in populations such as Pygmies with a high CCL3L1 gene dose and protective CCR5 genotypes, the spread of HIV might be minimal. Additionally, Pc, the critical vaccination proportion, an estimate of the fraction of the population that must be vaccinated successfully to eradicate an epidemic was <1 only when the infected partner had a protective CCL3L1-CCR5 genotype. Since in practice Pc cannot be >1, to prevent epidemic spread, population groups defined by specific CCL3L1-CCR5 genotypes might require repeated vaccination, or as our models suggest, a vaccine with an efficacy of >70%. Further, failure to account for CCL3L1-CCR5-based genetic risk might confound estimates of vaccine efficacy. For example, in a modeled trial of 500 subjects, misallocation of CCL3L1-CCR5 genotype of only 25 (5%) subjects between placebo and vaccine arms results in a relative error of ∼12% from the true vaccine efficacy.
CCL3L1-CCR5 genotypes may impact on the dynamics of the HIV epidemic and, consequently, the observed heterogeneous global distribution of HIV infection. As Ro is lowest when the infecting partner has beneficial CCL3L1-CCR5 genotypes, we infer that therapeutic vaccines directed towards reducing the infectivity of the host may play a role in halting epidemic spread. Further, CCL3L1-CCR5 genotype may provide critical guidance for optimizing the design and evaluation of HIV-1 vaccine trials and prevention programs.
Duffy antigen receptor for chemokines (DARC) expressed on red blood cells (RBCs) influences plasma levels of HIV-1-suppressive and proinflammatory chemokines such as CCL5/RANTES. DARC is also the RBC receptor for Plasmodium vivax. Africans with DARC −46C/C genotype, which confers a DARC-negative phenotype, are resistant to vivax malaria. Here, we show that HIV-1 attaches to RBCs via DARC, effecting trans-infection of target cells. In African Americans, DARC −46C/C is associated with 40% increase in the odds of acquiring HIV-1. If extrapolated to Africans, ∼11% of the HIV-1 burden in Africa may be linked to this genotype. After infection occurs, however, DARC-negative RBC status is associated with slower disease progression. Furthermore, the disease-accelerating effect of a previously described CCL5 polymorphism is evident only in DARC-expressing and not in DARC-negative HIV-infected individuals. Thus, DARC influences HIV/AIDS susceptibility by mediating trans-infection of HIV-1 and by affecting both chemokine-HIV interactions and chemokine-driven inflammation.
Whether vexing clinical decision-making dilemmas can be partly addressed by recent advances in genomics is unclear. For example, when to initiate highly active antiretroviral therapy (HAART) during HIV-1 infection remains a clinical dilemma. This decision relies heavily on assessing AIDS risk based on the CD4+ T cell count and plasma viral load. However, the trajectories of these two laboratory markers are influenced, in part, by polymorphisms in CCR5, the major HIV coreceptor, and the gene copy number of CCL3L1, a potent CCR5 ligand and HIV-suppressive chemokine. Therefore, we determined whether accounting for both genetic and laboratory markers provided an improved means of assessing AIDS risk.
Methods and Findings
In a prospective, single-site, ethnically-mixed cohort of 1,132 HIV-positive subjects, we determined the AIDS risk conveyed by the laboratory and genetic markers separately and in combination. Subjects were assigned to a low, moderate or high genetic risk group (GRG) based on variations in CCL3L1 and CCR5. The predictive value of the CCL3L1-CCR5 GRGs, as estimated by likelihood ratios, was equivalent to that of the laboratory markers. GRG status also predicted AIDS development when the laboratory markers conveyed a contrary risk. Additionally, in two separate and large groups of HIV+ subjects from a natural history cohort, the results from additive risk-scoring systems and classification and regression tree (CART) analysis revealed that the laboratory and CCL3L1-CCR5 genetic markers together provided more prognostic information than either marker alone. Furthermore, GRGs independently predicted the time interval from seroconversion to CD4+ cell count thresholds used to guide HAART initiation.
The combination of the laboratory and genetic markers captures a broader spectrum of AIDS risk than either marker alone. By tracking a unique aspect of AIDS risk distinct from that captured by the laboratory parameters, CCL3L1-CCR5 genotypes may have utility in HIV clinical management. These findings illustrate how genomic information might be applied to achieve practical benefits of personalized medicine.