Rise In CD4 Count Research Articles

Management of Opportunistic Infection Prophylaxis in the Highly Active Antiretroviral Therapy Era.

Prophylaxis and maintenance therapy against opportunistic infections are a mainstay of management of HIV-infected patients and have led to a significant improvement in quality of life and survival. Antiretroviral combination therapy (ART) has markedly changed the natural course of HIV infection. Incidence of opportunistic infections (OIs) has declined and survival after an OI has improved. Achieving a CD4 count of 200 cells/L after 6 months of ART is a valuable marker for low risk of OI afterwards. Therefore, recommendations on prophylaxis and maintenance therapy need to be redefined. Criteria for discontinuation, such as a CD4 count rise above threshold values and time above threshold values as response to ART, should be evaluated for the most frequent OIs. Reliable data in favor of discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia, toxoplasmic encephalitis, and Mycobacterium avium infection have been published. Discontinuation of maintenance therapy against P. carinii pneumonia is possible, and may be safe against cytomegalovirus retinitis, M. avium, and cryptococcosis and toxoplasmosis in selected patients. Pharmacologic interactions between drugs used for OI prophylaxis and antiretroviral drugs need to be taken into account.

Response to Highly Active Antiretroviral Therapy According to Duration of HIV Infection

Objective: To evaluate whether duration of HIV-1 infection influences the response to highly active antiretroviral therapy (HAART). Design: Prospective study of individuals (Italian Seroconversion Study cohort) with well-estimated dates of HIV-1 seroconversion. Methods: This analysis included 277 participants who began HAART (defined as three antiretroviral drugs used in combination). Cox regression models were used to evaluate the association between duration of infection (as categorical variable [≤3, 3-7.5, >7.5 years from seroconversion] or continuous variable) and an immunologic (rise in CD4 count >100 cells/mm3) and a virologic (decline in plasma HIV-RNA to unquantifiable levels) outcome. All analyses were stratified by center of recruitment and adjustment, when used, was for gender, age at inception of HAART, injection drug use, previous antiretroviral therapy, lag-time between positive and negative HIV test result, year of starting HAART, clinical stage, CD4 count, and HIV-RNA at time of HAART. Results: HAART was initiated a median of 6.4 years after seroconversion. There was a median follow-up of 1.6 years after starting HAART to the calendar cut-off (November 1999). One-hundred-eighty-one (65.3%) patients experienced a decline in viral load to below quantifiable levels and 184 (66.4%) experienced a rise in CD4 >100 cells/mm3. In the Cox models, by 1-year increase in duration of infection, we estimated a lower crude hazard of achieving a CD4 count increase >100 cells (relative hazard [RH], 0.96; 95% confidence interval [CI], 0.92-1.01; p = .09), and a lower hazard of reaching an unquantifiable level of plasma HIV-RNA (RH, 0.97; 95%CI, 0.93-1.02; p = .20). After adjustment, these values became 0.99 (95%CI, 0.93-1.04; p = .62) and 0.98 (95%CI, 0.93-1.04; p = .48), respectively. When duration of HIV infection was considered as a categorical variable, the results were consistent with those already described. Conclusions: These results suggest that the duration of HIV infection does not seem to play an important independent role in determining the virologic and immunologic responses to HAART.

Etiology and evaluation of diarrhea in AIDS:a global perspective at the millennium.

Etiology and evaluation of diarrhea in AIDS:a global perspective at the millennium.

HIV protease inhibitors, the lipodystrophy syndrome and polycystic ovary syndrome--is there a link?

A metabolic syndrome of insulin resistance, dyslipidaemia, central/visceral obesity, and peripheral lipodystrophy has been described with HIV protease inhibitors (PIs). A recent clinical presentation has led us to hypothesise that...

Cytomegalovirus retinitis after the initiation of highly active antiretroviral therapy: a 2 year prospective study

BACKGROUND/AIMSThere have been several recent reports suggesting that the natural history of cytomegalovirus retinitis (CMVR) has been significantly modified with the development of highly active antiretroviral therapy (HAART). This 2...

Determinants of sustainable CD4 lymphocyte count increases in response to antiretroviral therapy.

HIV-induced CD4 lymphocyte depletion is partially reversed by antiretroviral therapy but it is unclear if the degree to which the CD4 count rises depends on viral suppression (if so, the extent of viral suppression required to achieve a maximal CD4 count rise), whether the rise is sustainable and whether it occurs in patients with CD4 count <10 x 10(6) cells/l. We aimed to address these issues. We studied CD4 count and plasma HIV RNA values every 4 weeks for 72 weeks in 154 patients starting indinavir-containing regimens. Mean baseline HIV RNA and CD4 count were 4.8 log10 copies/ml and 180 x 10(6) cells/l, respectively. Overall, there was a mean increase in CD4 count of 143 x 10(6) cells/l by 72 weeks. The adjusted mean increase (adjusted for initial viral load, CD4 count and age) was strongly related to the mean viral suppression over the follow-up period (P < 0.0001). Importantly, there was a highly significant difference (P = 0.0004) in the rise in CD4 count between those with 2-3 log suppression (161 x 10(6) cells/l) and those with > 3 log suppression (314 x 10(6) cells/l; mean 3.6 log suppression in this group), suggesting that with even greater suppression the rise in CD4 lymphocytes may be still larger. We also studied whether CD4 counts were still rising after 72 weeks in patients with sustained suppression of at least 3 log in viral load. There was a significant (P = 0.004; paired t-test) rise in count of 43 x 10(6) cells/l between weeks 64 and 72 in these patients, suggesting that regeneration continues at least up to 72 weeks after therapy, provided virus replication continues to be suppressed. Patients with initial CD4 counts < 10 x 10(6) cells/l experienced no smaller rises than those at higher levels, even after adjustment for other factors. These results strongly support a direct causal relationship between HIV replication and CD4 lymphocyte count depletion. The rise in those with > 3 log suppression provides the best available indicator of the potential for natural CD4 regeneration in HIV-infected patients. However, since still greater CD4 count rises may be seen with more suppressive regimens, it may not be possible to study the intrinsic CD4 regenerative capacity until such regimens are available.

2·5 year remission of AIDS-associated progressive multifocal leukoencephalopathy with combined antiretroviral therapy

Progressive multifocal leukoencephalopathy (PML) results from infection of the central nervous system with JC virus, a papovavirus, which causes demyelination in the white matter of the brain. Long-term survival in AIDS patients with PML is rare. There is no consistently effective treatment although cytarabine, interferon, and zidovudine (AZT) may occasionally result in regression. We report remission of PML-associated hemiparesis for 104 weeks during combination antiretroviral therapy including a protease inhibitor. A 35-year-old man and previous intravenous drug user, was admitted due to worsening neurological symptoms, including dysarthria, aphasia, a right-sided facial droop, right arm weakness, and a walk that listed to the right. A T2weighted MRI scan showed confluent high signal intensity in the left centrum semiovale, left corona radiata with extension into the left internal capsule, left cerebral peduncle, and the pontine cortical spinal tracts (left figure). There was faint enhancement without mass effect. The MRI findings were characteristic of those observed with PML. No brain biopsy was done. Laboratory studies (ELISA and western blot) established the diagnosis of HIV infection. The CD4 count was 30 cells/μL and his HIV viral load was 189 900 copies/mL. He began zidovudine 200 mg three times daily and didanosine 200 mg twice daily as part of a controlled trial. Over the next 2–4 weeks the patient’s ability to convey thoughts quickly and to speak clearly improved. By the 10th week of antiretroviral therapy, he began an exercise regimen which included weight-lifting and aerobic activity and, by week 12, he was able to return to work as a fisherman. At week 24, indinavir, a protease inhibitor, was added (600 mg every 6 hours) to the anti-HIV regimen. By week 44, the CD4 count had increased to 230 cells/μL and the viral load was 240 copies/mL. A repeat MRI scan, 16 months after the first, demonstrated improvement in the extent of the T2 abnormalities (right figure). In none of the reported cases of long-term survival of patients treated with zidovudine or cytarabine was the remission as complete as the one cited here, although, since a biopsy was not done, it is possible that the initial presentation of aphasia and right arm weakness was not due to PML, but to an unusual manifestation of HIV. In previously reported cases, either the original symptoms were less severe or the resolution of neurological deficits was not as complete. Our patient has survived beyond the mean (over 2 years from the onset of symptoms) and has regained over 95% of his original function. This remission has been associated with improvement in immune function, evident by the rise in CD4 count. As more effective antiretroviral regimens become available, there may be more frequent remissions in persons with PML.

Consensus symposium on combined antiviral therapy; Overview of interferon and IL-2 combinations for the treatment of HIV infection

Among the immunomodulatory cytokines that have been evaluated for the treatment of HIV disease, α-interferon and interleukin-2 (IL-2) have been the most extensively studied. Monotherapy with α-interferon is effective therapy for HIV-associated Kaposi's sarcoma (KS) in patients with CD4 counts > 150 cells/mm 3. However, the doses necessary to achieve a significant anti-tumor effect are often poorly tolerated. Combination therapy with α-interferon and zidovudine is associated with dose-limiting toxicities and an anti-tumor effect similar to that of higher dose α-interferon monotherapy. The combination of α-interferon and zidovudine can synergistically inhibit HIV replication in vitro; however, in vivo results suggest the anti-HIV effect of this combination is no greater than that seen with zidovudine monotherapy. Whether combination of interferon-α and other antiviral drugs will be useful in the treatment of HIV infection remains to be seen. Recent studies employing intermittent courses of IL-2 combined with continuous antiretroviral therapy indicate that sustained rises in CD4 counts can be achieved. The ability of IL-2 therapy to result in a sustained rise in CD4 counts is critically dependent on the pre-treatment CD4 count. The immunologic and clinical significance of these IL-2-induced increases in CD4 counts is unknown. Larger, controlled trials are currently underway to evaluate the role of intermittent IL-2 therapy in HIV infection.

Zidovudine and Lamivudine

It has become apparent that the beneficial effects of zidovudine (AZT) and other antivirals will not continue indefinitely. However, synergistic activity of lamivudine (3TC) in combination with AZT, as well as reversal of phenotypic AZT resistance due to the presence of 3TC resistance-inducing mutations, has been documented in vitro. Two trials (NUCB 3001 and NUCB 3002) are therefore investigating the potential of the combination of 3TC with AZT. HIV-1-positive patients with CD4 cell counts of 100-400 cells/mm3 who had not previously received AZT were enrolled into study NUCB 3001 and treated with either AZT (200 mg t.i.d.) or 3TC (300 mg b.i.d.) plus AZT (200 mg t.i.d.) for 24 weeks. Open-label treatment with the combination regimen was offered for an additional 24 weeks. Both treatment groups experienced an initial increase in CD4 cell count. This increase was significantly greater and more sustained in the combination treatment group than in those receiving AZT monotherapy. Participants originally receiving AZT monotherapy, who changed to combination therapy after 24 weeks, experienced a rise in CD4 count. Those who began the study receiving combination therapy maintained their increased CD4 count for the duration of the study. A statistically significant difference in CD4 cell count between the two treatment groups was observed over the entire 48-week treatment period (p </= 0.0001) indicating that initial combination therapy was superior to monotherapy followed by a switch combination therapy after 24 weeks. Both treatment groups experienced a reduction in HIV-RNA levels and cellular viraemia, but these reductions were significantly greater in the combination treatment group than in those receiving AZT monotherapy. In addition, among patients initially randomized to AZT monotherapy, a significant reduction in the viral RNA concentration was observed after switching to combination therapy at week 24. There was an 80% reduction in p24 antigen levels from baseline in the combination treatment group compared with a 34% reduction from the baseline in the AZT monotherapy group, at 24 weeks. HIV-1-positive patients with CD4 cell counts of 100-400 cells/mm3 who had previously received a minimum of 24 weeks AZT treatment were enrolled into study NUCB 3002 and received either AZT monotherapy (200 mg t.i.d. plus placebo); AZT (200 mg t.i.d.) plus 3TC (300 mg b.i.d.) or AZT (200 mg t.i.d.) plus 3TC (150 mg b.i.d.) for 24 weeks. Open-label treatment with 3TC plus optional AZT was offered for a further 24 weeks (open-label phase). The study is still ongoing, but an initial increase in CD4 cell count was observed in the combination groups whereas, in the AZT monotherapy group, no discernible increase in CD4 cell count was observed at any time. The favorable effect of combination treatment with AZT and 3TC on CD4 cell count persisted throughout the open-label phase of the study. The addition of 3TC to the treatment regimens of patients who initially received AZT monotherapy had a favorable effect on CD4 cell count. Combination treatment with 3TC and AZT also resulted in a significantly greater reduction in viral load compared with AZT monotherapy. In conclusion, combination therapy with AZT plus 3TC produces beneficial effects on CD4 cell counts, HIV-1 RNA levels, and p24 antigen levels, which appear to be greater and more sustained than those produced by AZT monotherapy or any combination therapy to date. This combination appears to offer increased efficacy compared with AZT monotherapy without an increased risk of adverse experiences. Future studies to identify those patients most likely to benefit from such treatment and the optimum time for its initiation are therefore warranted.

Race Joins Host of Unanswered Questions on Early HIV Therapy

EARLY INTERVENTION harm African Americans infected with the human immunodeficiency virus (HIV), according to a fragile new finding. The data, which come from a post hoc subset analysis not in the study's original design, may be artifactual and not truly result from a biological effect, cautions John D. Hamilton, MD, cochair of the study and chief of infectious disease at the Durham (NC) Veterans Affairs (VA) Medical Center. Progression to acquired immunodeficiency syndrome (AIDS) and death was higher in blacks given zidovudine (Retrovir [commonly called AZT], Burroughs Wellcome Co) when their CD4 counts were between 200 and 500 mm 3 than in patients who were not given the drug until their CD4 counts dropped below 200 mm 3 . Blacks also did not have the highly significant CD4 count rise seen in whites when zidovudine therapy is begun, says Hamilton. He presented the findings from the 4-year study, in which