Immunological response to highly active antiretroviral therapy in children with clinically stable HIV-1 infection

We studied changes in 60 immunological parameters after the administration of highly active antiretroviral therapy (HAART) in 192 clinically stable antiretroviral drug-experienced HIV-1-infected children 4 months-17 years old. The studied immunological parameters included standard lymphocyte subsets and lymphocyte surface markers of maturation and activation. The most significant changes during the 48-week study period were seen for CD8(+), CD8(+)CD62L(+)CD45RA(+), CD8(+)CD38(+)HLA-DR(+), and CD4(+) T cell percentages (P < .0001 for all parameters). These changes suggest that significant decreases in the expression of activation markers and increases in the expression of naive markers in the CD8(+) T cell population may be related to better virologic control in these HIV-1-infected children, who had relatively stable immune function at the initiation of HAART. At week 44 of HAART, the major immunological parameters in these HIV-1-infected children moved from baseline values to about halfway to two-thirds of the way toward the values in healthy, uninfected children.     

Gammadelta T cell activation by chronic HIV infection may contribute to intrahepatic vdelta1 compartmentalization and hepatitis C virus disease progression independent of highly active antiretroviral therapy

HIV and hepatis C virus (HCV) coinfection is frequently associated with rapid progression of HCV-related disease, resulting in a higher risk of cirrhosis. Data suggest that natural T cells expressing the Vdelta1 T cell receptor rearrangement are recruited in the liver of chronically HCV-infected patients and are increased in the peripheral blood of HIV-infected persons. We studied gammadelta T cell distribution in the peripheral blood and liver of HCV-infected and HIV/HCV-coinfected patients in the presence and absence of antiretroviral therapy. We observed that Vdelta1+ T cells releasing helper T cell type 1 cytokines are compartmentalized not only in the liver of HCV+ patients, but also of HIV/HCV-coinfected persons. HIV/HCV patients showed an increased frequency of both peripheral and intrahepatic Vdelta1 natural T lymphocytes, resulting in a higher degree of hepatic inflammation when compared with patients with other liver diseases. Finally, highly active antiretroviral therapy (HAART) was unable to restore Vdelta1T cell circulation to normal levels in chronically HIV-infected persons. We conclude that gammadelta T lymphocytes released from tissue to the bloodstream circulation under the influence of chronic HIV infection may contribute to intrahepatic Vdelta1 compartmentalization and progression of liver disease, independently of HAART.     

Effect of hepatitis C infection on progression of HIV disease and early response to initial antiretroviral therapy

OBJECTIVES: To describe the effect of hepatitis C virus (HCV) on the progression of HIV disease and on early changes in the CD4 cell count and HIV viral load after HAART initiation. DESIGN AND METHODS: Data were from a longitudinal medical records review project conducted in over 100 US medical clinics from 1998 to 2004. We analysed data from HIV-infected patients who received antiretroviral therapy (ART), calculated adjusted hazard ratios describing the hazard of death or progression to an AIDS-defining opportunistic illness (AIDS-OI) associated with prevalent HCV infection, and estimated the change in CD4 cell count and HIV viral load after HAART initiation, stratified by HCV status. RESULTS: A total of 10 481 HIV-infected individuals were followed for a median of 1.9 years; 19% had HCV. HCV infection was not associated with progression to AIDS-OI or death after controlling for important confounding conditions. Factors significantly confounding the risk of both death and diagnosis of an AIDS-OI were alcoholism, drug-induced hepatitis, and the type of ART prescribed. Acute and chronic hepatitis B infection confounded the risk of AIDS-OI diagnosis. During the 12 months after starting HAART, proportional increases in CD4 cell counts did not differ between HCV-infected and HCV-uninfected individuals. Likewise, the short-term change in viral load did not differ. CONCLUSION: In our cohort, HCV did not increase the risk of death or AIDS-OI, and did not affect the early immunological or virological response to initial HAART. Clinicians should evaluate patients with HCV for other, manageable problems, including alcoholism and other viral hepatitis.     

The effect of hepatitis C on progression to AIDS before and after highly active antiretroviral therapy

OBJECTIVES: To assess the effect of infection with hepatitis C virus (HCV) on the progression of human immunodeficiency virus (HIV) disease, before and after the introduction of highly active antiretroviral therapy (HAART). METHODS: We used data from a multi-centre prospective study of HIV seroconverters. Survival analyses were performed to compare the progression to AIDS by HCV serostatus in the period before HAART (i.e. June 1991-May 1996) and in the HAART era (i.e. June 1996-June 2001), controlling for duration of HIV infection. RESULTS: Among the 1052 persons enrolled, 595 (56.6%) were co-infected; the median follow-up time was 9.7 years. Adjusting for demographic variables (age at HIV seroconversion and gender), HCV infection had no effect on the progression to AIDS in the pre-HAART era [relative hazard (RH) = 0.84; 95% confidence interval (CI), 0.63-1.11], whereas it increased the risk in the HAART era (RH = 1.77; 95% CI, 1.15-2.73). In the HAART era, the proportion of person-time spent on HAART out of the total time at risk was significantly lower among co-infected persons (30 versus 40% for non-co-infected persons; P-value = 0.001); no significant difference was found for dual-therapy (29 versus 25%, respectively; P-value = 0.205); a significant difference was found for mono-therapy (15 versus 8%, respectively; P-value < 0.001). CONCLUSIONS: HCV infection was not a determinant of HIV disease progression in the pre-HAART era, whereas since the introduction of HAART, co-infected individuals seem to have had a faster disease progression. This may in part be explained by differences in person-time spent on different antiretroviral regimens.     

Comparative response of African HIV-1-infected individuals to highly active antiretroviral therapy

OBJECTIVE: Few data exist on the virological response to antiretroviral therapy of individuals infected with African HIV-1 subtypes. Our objective was to compare the response, in our clinic, of African HIV-1-infected patients with their British and European contemporaries treated with the same regimes. DESIGN: The St Mary's Hospital HIV database was used to identify drug-naive African and European patients starting a highly active antiretroviral therapy (HAART) regimen. METHODS: HIV-1 subtype was determined by phylogenetic analysis of pol sequences. Kaplan-Meier survival analysis was used to estimate the proportion of patients achieving undetectable viral loads (< 500 copies/ml). The longer-term response to therapy was assessed by changes in CD4 cell counts and viral loads from baseline. RESULTS: A total of 265 patients were classified as 'European' and 97 as 'African', confirmed by sequence. The time to first undetectable viral load was similar for the two groups (P = 0.9). Although there were no statistically significant differences in the CD4 cell count responses (P = 0.11), there was evidence of an increase in viral load after 9 months for the African group, resulting in a widening viral load gap between the two cohorts; the effect of ethnic group was statistically significant (P < 0.001). CONCLUSION: The initial virological and immunological responses of the African and European cohorts to HAART were similar; although the longer-term virological response was poorer in the African cohort, which may be related to adherence. On the basis of these findings, there is no justification for withholding HAART from Africa on virological grounds.     

Impact of highly active antiretroviral therapy on organ-specific manifestations of HIV-1 infection

In the last 10 years, interesting results have been reported concerning the impact of highly active antiretroviral therapy (HAART) on the changing pattern of organ-specific manifestations of HIV-1 infection. There has been a clear step-wise reduction in the incidence of several opportunistic infections (OIs), particularly Pneumocystis carinii pneumonia, whereas a nonsignificant reduction in incidence has been observed for other organ-specific diseases, including invasive cervical cancer and Hodgkin disease. In addition, several organ-specific manifestations, including HIV-associated nephropathy, wasting syndrome and cardiomyopathy, are a direct consequence of damage by HIV-1, and so HAART may have a therapeutic effect in improving or preventing these manifestations. Finally, the introduction of HAART has seen the emergence of several complications, termed immune reconstitution inflammatory syndrome, which includes OIs such as cytomegalovirus vitritis, Mycobacterium avium complex lymphadenitis, paradoxical responses to treatment for tuberculosis, and exacerbation of cryptococcosis. Because not all HIV-1 organ-specific manifestations are decreasing in the HAART era, this review will analyse the influence of HAART on several organ-specific manifestations, and in particular OIs related to several organs, cerebral disorders and HIV-1-related neoplasia.     

Hepatitis B and C virus co-infection and the risk for hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection

OBJECTIVE: To investigate the risk of hepatotoxicity after initiation of protease inhibitor-containing highly active antiretroviral therapy (HAART) for HIV-1 infected patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) co-infection. DESIGN: Retrospective study with 394 HIV-1-infected patients initiating HAART at a single university clinic. METHODS: Liver enzyme elevation (LEE) was defined as alanine aminotransferase or aspartate aminotransferase at least five times the upper limit of normal and an absolute increase of > 100 U/l. Relative risks for time to LEE were estimated using Cox proportional hazards models. RESULTS: Of 394 patients 7% were hepatitis B surface antigen (HBsAg)-positive and 14% were anti-HCV-positive. Patients with chronic hepatitis had a higher risk for LEE compared with patients without co-infection: 37% versus 12% respectively. After adjustment for higher baseline transaminases, the presence of HBsAg or anti-HCV remained associated with an increased risk of LEE - relative risk 2.78 (95% confidence interval, 1.50-5.16) and 2.46 (95% confidence interval, 1.43-4.24) respectively. In patients with LEE, transaminases declined whether HAART was continued or modified. Of patients with chronic HBV infection 38% lost HBeAg or developed anti-HBe after initiation of HAART, and one seroconverted from HBsAg-positive to anti-HBs-positive. However, there was no clear relationship with LEE. CONCLUSIONS: HIV-1-infected patients co-infected with HBV or HCV were at considerably higher risk of developing LEE when HAART was initiated compared with patients without co-infection, but it is usually not necessary to modify antiretroviral therapy.     

Evidence of thymic reconstitution after highly active antiretroviral therapy in HIV-1 infection

Objectives

We aimed to provide evidence of thymic reconstitution after highly active antiretroviral therapy (HAART) in HIV‐1 infected patients and to correlate this with the restoration of peripheral naïve T cells.

Methods

Positron emission tomography (PET) enables definitive evidence of thymic activity, indicating functional potential. In this case study, a single patient who initiatiated HAART demonstrated reconstitution of the naïve T‐cell pool and underwent thymic PET scans at baseline and 2 and 6 months following initiation of therapy. Two patients who failed to demonstrate such reconstitution acted as controls. These patients (mean age 27 years) had chronic HIV infection with low CD4 T‐cell counts (mean 82, range 9–160 cells/μL blood). Increased function of the thymus visualized by PET was correlated with phenotypic changes in CD4 and CD8 T cells in the periphery measured by flow cytometry, and with numbers of recent thymic emigrants measured by quantification of the numbers of T‐cell receptor excision circles (TRECs) in peripheral cells.

Results

In one patient, clear correlations could be drawn between visible activity within the thymus, as measured by increased [F18]fluorodeoxyglucose (FDG) uptake, and regeneration of naïve CD4 (CD45RA/CD62L) T cells, increased numbers of CD4 T cells, controlled viraemia and increased numbers of recent thymic emigrants. A second patient displayed no increase in peripheral CD4 count and no increase in thymic activity. The third patient elected to stop therapy following the 2‐month time point.

Conclusions

The use of PET suggests that thymic activity may increase after HAART, indicating that the thymus has the potential to be functional even in HIV‐1 infected persons with low CD4 T‐cell counts.

     

Effect of highly active antiretroviral therapy on cervicovaginal HIV-1 RNA

OBJECTIVES: To determine the frequency of cervicovaginal lavage and plasma HIV-1 RNA levels that are below detectable levels (< 400 copies/ml) among women on highly active antiretroviral therapy (HAART), non-HAART and on no therapy. To compare the effect of initiating HAART on the timing of HIV-1 RNA suppression in the blood plasma and genital tract among antiretroviral-na?ve women. METHODS: Data were obtained from 205 HIV-infected women with paired plasma and cervicovaginal lavage viral load measurements. Seven antiretroviral-na?ve women starting HAART had viral load measurements performed daily for one week, at 2 weeks and at 1 month after initiating therapy. Viral load quantification was carried out by nucleic acid sequence-based amplification assay. The lower limit of detection was 400 copies/ml. RESULTS: Plasma and cervicovaginal HIV-1 RNA was detectable in 71 and 26% of the women, respectively. Among women with plasma viral loads less than 400, 400-9999, and 10,000 copies/ml or over, genital tract HIV-1 RNA was detected in 3, 17 and 48%, respectively (P < 0.001). Fifty-one per cent of the women with CD4 cell counts of less than 200/mm3 had detectable cervicovaginal viral loads compared with 18% among women with CD4 cell counts of 200/mm3 or over (P < 0.001). Cervicovaginal HIV-1 RNA was less than 400 copies/ml in 85% of those on HAART, 69% of those on non-HAART and 69% of those on no therapy (P < 0.045). In seven antiretroviral-na?ve women initiating HAART, cervicovaginal HIV-1 RNA decreased by 0.7-2.1 log10 within 1-14 days of starting therapy. CONCLUSION: The cervicovaginal HIV-1 RNA level was positively correlated with plasma HIV-1 RNA and negatively with the CD4 cell count. The use of HAART was significantly associated with below-detectable levels of HIV-1 RNA in both plasma and the genital tract. HIV-1 RNA suppression in the genital tract may occur rapidly after initiating therapy.     

Clinical progression of hepatitis C virus-related chronic liver disease in human immunodeficiency virus-infected patients undergoing highly active antiretroviral therapy

Little is known about the natural history of liver disease in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected subjects under highly active antiretroviral therapy (HAART). The objectives of this study were to obtain information about the mortality, the incidence of hepatic decompensations, and the predictors thereof in this population. In a multicenter cohort study, the time to the first hepatic decompensation and the survival of 1,011 antiretroviral na?ve, HIV/HCV-coinfected patients who started HAART and who were followed prospectively were analyzed. After a median (Q1-Q3) follow-up of 5.3 (2.9-7.1) years, 59(5.83%) patients developed a hepatic decompensation and 69 (6.82%) died, 30 (43%) of them because of liver disease. The factors independently associated [HR (95% CI)] with the occurrence of hepatic decompensations were age older than 33 years [2.11 (1.18-3.78)], female sex [2.11 (1.07-4.15)], Centers for Disease Control stage C [2.14 (1.24-3.70)], a diagnosis of cirrhosis at baseline [10.86 (6.02-19.6)], CD4 cell gain lower than 100/mm3 [4.10 (2.18-7.69)] and less than 60% of the follow-up with undetectable HIV viral load [5.23 (2.5-10.93)]. Older age [2.97 (1.18-7.50)], lack of HCV therapy [11.32 (1.44-89.05)], hepatitis D virus coinfection [16.15 (2.45-106.48)], a diagnosis of cirrhosis at recruitment [13.69 (5.55-34.48)], hepatic encephalopathy [62.5 (21.27-200)] and lower CD4 cell gain [3.63 (1.45-9.09)] were associated with mortality due to liver failure. CONCLUSION: End-stage liver disease is the primary cause of death in HIV/HCV-coinfected patients under HAART. Higher increase of CD4 cell counts, lack of markers of serious liver disease and therapy against HCV are factors associated with better hepatic outcome.     

Immunological and virological impact of highly active antiretroviral therapy initiated during acute HIV-1 infection

The immunological and virological impact of short-term treatment initiated during acute human immunodeficiency virus type 1 (HIV-1) infection was assessed prospectively in 20 subjects, 12 of whom initiated highly active antiretroviral therapy (HAART) for 24 weeks and then terminated treatment. Treatment resulted in suppression of viremia, an increase in the CD4+ T cell count, enhanced differentiation of HIV-1-specific CD8(+) T cells from effector memory to effector cells at week 24 of HAART, and significantly higher virus-specific interferon- gamma+ CD8+ T cell responses after viral rebound (at week 48). However, despite these immunological changes, no differences in viremia or in the CD4+ T cell count were found 6 months after HAART was stopped, when treated subjects were compared with untreated subjects.     

Gender differences in clinical progression of HIV-1-infected individuals during long-term highly active antiretroviral therapy

OBJECTIVE: To assess gender differences in the long-term clinical, virological and immunological outcomes during highly active antiretroviral therapy (HAART). METHODS: This longitudinal observational multicentre study followed 2460 HIV-infected patients who had begun a protease inhibitor-based regimen for a median period of 43 months. Outcome measures were virological suppression (< 500 copies/ml), confirmed virological rebound after suppression, and death or new AIDS-defining illness (ADI). RESULTS: At baseline, 690 female patients (28.0%) had significantly lower age, higher prevalence of heterosexual contact and lower prevalence of intravenous drug use as risk factors for HIV infection compared with males. Furthermore, females had a lower number of AIDS-defining illnesses, higher CD4 cell counts and lower viral loads.No gender differences were reported in terms of proportion of patients achieving viral suppression or exhibiting rebound after achieving viral suppression. Female patients experienced reduced clinical progression during follow-up compared with males (P = 0.008) by Kaplan-Meier analysis; however this difference was not significant in an adjusted analysis. In a multivariate model, the interaction between gender and risk factor for HIV or viral load showed that female drug users and female patients with a baseline HIV RNA viral load of 10(4)-10(5) copies/ml had a favourable clinical outcome compared with males (P = 0.035 and P = 0.015, respectively). CONCLUSION: No differences were found between genders in terms of virological and immunological outcomes during long-term HAART. Nevertheless, a lower risk of clinical progression was reported among female patients with intermediate baseline viral load than in males.     

Immune restoration in human immunodeficiency virus and hepatitis C virus coinfected patients after highly active antiretroviral therapy

ObjectiveTo evaluate the influence of hepatitis C virus on immunological and virological responses after highly active antiretroviral therapy initiation in human immunodeficiency virus/hepatitis C virus coinfected patients compared to monoinfected human immunodeficiency virus-infected patients.MethodsThe study enrolled 65 human immunodeficiency virus-1-infected subjects who initiated highly active antiretroviral therapy and attended follow-up visits over 48 weeks from 2008 to 2010. They were grouped based on hepatitis C virus-RNA results. Virological and immunological responses were monitored at baseline and at the end of weeks 12, 24, 36, and 48.ResultsThere were 35 human immunodeficiency virus monoinfected and 30 human immunodeficiency virus/hepatitis C virus coinfected patients. In the present study human immunodeficiency virus/hepatitis C virus coinfection did not seem to influence CD4 T-lymphocytes recovery. There was no difference between the curves of CD4 T-lymphocytes raise of coinfected and monoinfected groups.ConclusionThis prospective study confirms that hepatitis C virus infection does not seem to be associated with impaired CD4 T-lymphocytes recovery after HAART.     

HIV-1 RNA, CD4 T-lymphocytes, and clinical response to highly active antiretroviral therapy.

OBJECTIVE: To determine if HIV-1 RNA and CD4 lymphocyte thresholds for the initiation of highly active antiretroviral therapy (HAART) are associated with clinical response to therapy. DESIGN: Observational cohort study. SETTING: Johns Hopkins Hospital HIV Clinic. PATIENTS: HIV-infected adults. INTERVENTION: Patients initiating HAART (n = 530) were compared with concurrent patients who did not receive HAART (n = 484). MAIN OUTCOME MEASURE: Progression to a new AIDS-defining illness or death. RESULTS: The average duration of follow-up for the cohort was 22 months. HAART resulted in decreased disease progression among persons with fewer than, but not more than, 200 x 10(6) CD4 lymphocytes/l prior to treatment. Among persons receiving HAART, plasma HIV-1 RNA level prior to therapy was not associated with HIV disease progression within CD4 T-lymphocyte count strata. In a Cox multivariate proportional hazards model that adjusted for age, sex, race, prior opportunistic infection, and CD4 T lymphocytes, < or = 200 x 10(6) CD4 lymphocytes/l was the strongest predictor of disease progression. HIV-1 RNA level prior to starting HAART of < 5000 copies/ml, 5001-55 000 copies/ml, or > 55 000 copies/ml was not associated with disease progression on therapy, particularly among persons with > 200 x 10(6) CD4 lymphocytes/l. There was no sex difference in disease progression on treatment. CONCLUSIONS: Our data suggest that current guidelines for initiating HAART should place greater emphasis on CD4 lymphocyte than HIV-1 RNA level for both men and women. Further longitudinal follow-up will be needed to better ascertain whether HAART initiated at > 200 x 10(6) CD4 lymphocytes/l is effective in slowing disease progression.     

Effects of highly active antiretroviral therapy on HIV-1-associated oral complications

The oral cavity of human immunodeficiency virus type I (HIV-1) infected individuals is subjected to a series of opportunistic infections which are usually considered as a prognostic marker for the severity of infection as well as an indicator of immunodeficiency. The highly active antiretroviral therapy (HAART) has significantly lessened the severity of HIV-associated oral infections although this therapeutic regimen is considered to be responsible for some of the oral lesions such as oral warts and salivary gland disorders. In addition, the beneficial effects of HAART on HIV associated oral lesions are stratified with age, with the adult population showing improvements whereas the oral lesions among children remain unchanged with this therapy. The presence of HIV-1 in the saliva, and infectivity of oral epithelial cells suggest that the oral cavity is a site of HIV pathogenesis and potential reservoir for the disease in the setting of virally suppressive HAART. Overall HIV associated oral lesions are usually due to fungal, bacterial, and viral infections as well as some of unknown etiology. This review describes the current status of HIV associated oral lesions by comparing historically available pre-HAART data. Future directions envisioned by the National Institutes of Health as well as novel avenues to be explored are also presented.