Is antiretroviral treatment of primary HIV infection clinically justified on the basis of current evidence?
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Acute Disease↗
Biomedical subjects
David A Cooper
Publications and source records attributed to David A Cooper.
Efficacy of tenofovir disoproxil fumarate in antiretroviral therapy-naive and -experienced patients coinfected with HIV-1 and hepatitis B virus.
BACKGROUND: Coinfection with human immunodeficiency virus type 1 (HIV-1) increases the risk of hepatitis B virus (HBV)-associated progressive liver disease. Lamivudine has potent activity against both HIV-1 and HBV; however, lamivudine-resistance mutations in HBV frequently develop. METHODS: Substudies of the safety and efficacy of tenofovir disoproxil fumarate (tenofovir DF) for patients coinfected with HIV and HBV were undertaken within 2 phase 3 randomized controlled trials involving antiretroviral therapy-experienced (study 907) and -naive (study 903) HIV-infected populations. Inclusion criteria were detection of hepatitis B surface antigen, an HBV DNA level >106 copies/mL at baseline, and HBV DNA specimens available at week 24 (study 907) and week 48 (study 903). RESULTS: In study 907, the mean decrease in HBV DNA was 4.9 log(10), after 24 weeks, for 10 patients randomized to receive tenofovir DF, compared with a mean increase of 1.2 log(10) for 2 patients randomized to receive placebo (P=.041). The mean decrease in HBV DNA during tenofovir DF treatment was similar for patients with wild-type (5.3 log(10)) and lamivudine-resistant (4.6 log(10)) HBV strains. In study 903, the mean decrease in HBV DNA was 3.0 log(10), after 48 weeks, for 6 patients randomized to receive lamivudine, compared with 4.7 log(10) for 5 patients randomized to receive lamivudine and tenofovir DF (P=.055). Four patients developed tyrosine-methionine-aspartate-aspartate mutations, all in the lamivudine-only treatment arm. CONCLUSION: Tenofovir DF has potent anti-HBV efficacy in antiretroviral therapy-experienced and -naive individuals coinfected with HIV and HBV.
Adenine↗
No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind, placebo-controlled trial.
BACKGROUND: Lipodystrophy commonly complicates antiretroviral therapy of HIV-1 infection. Thiazolidinediones such as rosiglitazone promote subcutaneous fat growth in type 2 diabetics and adults with congenital lipodystrophy, and can prevent HIV-1 protease inhibitor toxicity to adipocytes in vitro. We postulated that rosiglitazone would improve HIV lipoatrophy. METHODS: 108 HIV-1-infected lipoatrophic adults on antiretroviral therapy were randomised to rosiglitazone 4 mg twice daily (n=53) or matching placebo (n=55) for 48 weeks. The study had 80% power to detect a 0.5 kg difference in changes in limb fat (using dual-energy X-ray absorptiometry) between groups at week 48 by intention-to-treat analysis, and a 0.7 kg difference within each protease inhibitor stratum. FINDINGS: Limb fat increased by 0.14 kg in the rosiglitazone group and 0.18 kg in the placebo group (mean difference -0.04 kg [95%CI -0.29 to 0.21]; p=0.74 by t test), with three participants (one on rosiglitazone and two controls), lost to follow-up. Rosiglitazone had no significant benefit on any other measure of lipodystrophy, despite large relative increases in plasma adiponectin (4.2 mmol/L [102%]; p<0.0001) and in three markers of insulin sensitivity (p=0.01 to 0.02). Six participants ceased study drug in each group, four participants (three on rosiglitazone and one control) for related adverse events. The main adverse effects, which seem to be almost unique to this population, were asymptomatic hypertriglyceridaemia (mean relative increase 0.9 mmol/L at week 48; p=0.04) and hypercholesterolaemia (1.5 mmol/L; p=0.001). INTERPRETATION: Rosiglitazone for 48 weeks did not improve lipoatrophy in HIV-1-infected adults receiving antiretroviral therapy. Use of less toxic antiretroviral treatment is necessary to prevent lipoatrophy.
Anemia↗
Peptide inhibitors of virus-cell fusion: enfuvirtide as a case study in clinical discovery and development.
The peptidic antiretroviral enfuvirtide (Fuzeon) is the first clinically approved antiviral fusion inhibitor and the first antiretroviral that must routinely be administered parenterally. Its extracellular activity results both in activity against current drug-resistant strains of HIV-1 and a low potential for systemic toxicities. As a peptide, enfuvirtide also exhibits few interactions with other antiretrovirals and concomitant medications used in HIV disease. Enfuvirtide shows potent antiretroviral activity and significantly improves medical outcomes in highly treatment-experienced patients with HIV-1 infection, but like other antiretrovirals must be given as part of a carefully selected combination regimen to minimise the risk of emergent drug resistance. Despite its subcutaneous route of administration, clinical data indicate that most patients can accept long-term enfuvirtide treatment with little difficulty or impact on daily activities. The only common adverse event associated with enfuvirtide use is injection-site reactions of generally mild-to-moderate severity, which are seldom treatment-limiting.
Acquired Immunodeficiency Syndrome↗
Frequent transmission of cytotoxic-T-lymphocyte escape mutants of human immunodeficiency virus type 1 in the highly HLA-A24-positive Japanese population.
Although Japan is classified as a country with a low prevalence of human immunodeficiency virus type 1 (HIV-1), domestic sexual transmission has been increasing steadily. Because 70% of the Japanese population expresses HLA-A24 (genotype HLA-A*2402), we wished to assess the effect of the dominant HLA type on the evolution and transmission of HIV-1 among the Japanese population. Twenty-three out of 25 A24-positive Japanese patients had a Y-to-F substitution at the second position [Nef138-10(2F)] in an immunodominant A24-restricted CTL epitope in their HIV-1 nef gene (Nef138-10). None of 12 A24-negative Japanese hemophiliacs but 9 out of 16 patients infected through unprotected sexual intercourse had Nef138-10(2F) (P < 0.01). Two of two A24-positive but none of six A24-negative Australians had Nef138-10(2F). Nef138-10(2F) peptides bound well to the HLA-A*2402 heavy chain; however, Nef138-10(2F) was expressed poorly on the cell surface from the native protein. Thus, HIV-1 with Nef138-10(2F) appears to be a cytotoxic-T-lymphocyte escape mutant and has been transmitted frequently by sexual contact among the highly A24-positive Japanese population.
Amino Acid Sequence↗
Identification of circulating antigen-specific CD4+ T lymphocytes with a CCR5+, cytotoxic phenotype in an HIV-1 long-term nonprogressor and in CMV infection.
Antigen-specific CD4+ effector T cells primarily provide help for B-cell antibody responses and CD8+ cytotoxic T-lymphocyte (CTL) responses. We have found an expanded population of HIV-1 p24-specific, T-cell receptor V beta 17+, CD4+ T lymphocytes, defined by in vitro proliferative and interferon-gamma responses to a 15-mer Gag peptide, in the peripheral blood of an individual with long-term nonprogressive HIV-1 infection. Ex vivo, these cells were CCR5+ and CCR7-, consistent with an effector/memory function. Surprisingly, these cells highly expressed several proteins characteristic of cytotoxic lymphocytes, including TIA-1 (T-cell intracellular antigen 1; GMP-17/NKG7), granzymes A and B, CD161 (NKRP-1), and CD244 (C1.7/2B4). Following in vitro peptide stimulation, these cells produced interleukin 2 (IL-2) and intracellular CD40L, suggesting possible helper function, in addition to induction of perforin and cytotoxicity. A subset of cytomegalovirus (CMV)-specific CD4+ T cells in healthy adults similarly expressed these CTL markers and CCR5, ex vivo. Furthermore, this distinct subset of CD4+ T cells was significantly elevated in healthy CMV-seropositive adults, compared with CMV-seronegative individuals. These results suggest that CCR5+ CD4+ CTL may be a major effector mechanism of the immune response to viral infections in humans. Moreover, expression of CCR5 may render them particularly susceptible to cytopathic effects during progressive HIV-1 infection.
Adult↗
Risk of severe hepatotoxicity associated with antiretroviral therapy in the HIV-NAT Cohort, Thailand, 1996-2001.
OBJECTIVE: To examine rates and predictors of severe hepatotoxicity with combination antiretroviral therapy in a developing country setting: the eight HIV-NAT randomized controlled trials in Thailand. METHODS: All patients (n = 692) received at least two nucleoside reverse transcriptase inhibitors; 215 also received a non-nucleoside reverse transcriptase inhibitor (NNRTI) and 135 also received a protease inhibitor. Severe hepatotoxicity was defined as an increase in alanine aminotransferase (ALT) level to five times the upper limit of normal and an increase of at least 100 U/l from baseline. Liver function tests were available at baseline and weeks 4, 8, 12, 24, 36 and 48. Hepatitis B virus (HBV) and hepatitis C virus (HCV) testing was performed on stored serum. RESULTS: Mean age was 32.3 years; 52% were male, 11% had Centers for Disease Control and Prevention category C HIV disease at baseline, and 22% had received prior antiretroviral therapy. Prevalence of HBV, HCV and HBV/HCV coinfection was 8.7%, 7.2%, and 0.4%, respectively. Incidence of severe hepatotoxicity was 6.1/100 person-years [95% confidence interval (CI), 4.3-8.3/100]. In multivariate analysis, predictors of severe hepatotoxicity were HBV or HCV coinfection, and NNRTI-containing therapy. Incidence of severe hepatotoxicity was particularly high among patients receiving nevaripine (18.5/100 person-years; 95% CI, 11.6-27.8) and nevirapine/efavirenz (44.4/100 person-years; 95% CI, 12.1-113.7). CONCLUSIONS: Incidence and risk factors for severe hepatotoxicity appear similar among these Thai patients to those in other racial groups. Development of standardized antiretroviral therapy regimens for developing country settings should consider potential toxicity and capabilities for monitoring of toxicity.
Adult↗
Pharmacokinetics of indinavir/ritonavir (800/100 mg) in combination with efavirenz (600 mg) in HIV-1-infected subjects.
BACKGROUND: Addition of efavirenz (600 mg) to indinavir/ritonavir (800/100 mg) results in significant decreases in indinavir levels in healthy volunteers. This study evaluated the steady-state pharmacokinetics of indinavir/ritonavir at 800/100 mg twice daily (bid) in combination with efavirenz at 600 mg once daily (qd) in HIV-infected Thai subjects who used this nucleoside-sparing combination in The HIV Netherlands Australia Thailand Research Collaboration 009 study. METHODS: At week 4 of the study, 12-hour pharmacokinetic profiles for indinavir/ritonavir were obtained for 20 HIV-infected subjects. For efavirenz, the concentrations at 12 hours and 24 hours (Cmin) after dosing were assessed. RESULTS: All subjects (10 males and 10 females) completed the study. The geometric mean area under the concentration versus time curve, Cmin, and maximum plasma concentration of indinavir were 45.7 mg/(L. h) (95% confidence interval [CI], 39.8-52.5), 0.32 mg/L (95% CI, 0.24-0.44), and 11.1 mg/L (95% CI, 9.4-13.0), respectively. A >10-fold variation in indinavir Cmin was observed. All subjects had an indinavir Cmin that was at least comparable with the reported mean population Cmin of indinavir at 800 mg thrice daily without ritonavir (0.15 mg/L). The geometric mean concentration at 12 hours and Cmin of efavirenz were 3.1 mg/L (95% CI, 2.5-3.7) and 2.1 mg/L (95% CI, 1.6-2.6), respectively. CONCLUSIONS: Despite the known pharmacokinetic interaction between efavirenz and indinavir/ritonavir, the combination of indinavir/ritonavir at 800/100 mg bid and efavirenz at 600 mg qd results in adequate minimum concentrations of both indinavir and efavirenz for treatment-naive patients.
Acquired Immunodeficiency Syndrome↗
Polyclonal proliferation and apoptosis of CCR5+ T lymphocytes during primary human immunodeficiency virus type 1 infection: regulation by interleukin (IL)-2, IL-15, and Bcl-2.
We measured apoptosis of subsets of T lymphocytes by single-cell analysis of caspase activation, to confirm high turnover of chemokine receptor CCR5(+) T cells in subjects with acute, primary human immunodeficiency virus type 1 (HIV-1) infection (PHI). High levels of spontaneous apoptosis, consisting mainly of CD8(+) T lymphocytes, were closely associated with increases in the activation markers Ki-67, CD38, and the HIV coreceptor CCR5 and with decreases in Bcl-2 and the interleukin (IL)-7 receptor at the single-cell level. Increased expression of Ki-67 and CCR5 ex vivo, as well as increased apoptosis, was seen in all T cell receptor beta-chain variable region (TCRBV) subfamilies studied. The addition of IL-2 or IL-15, but not IL-7, significantly inhibited caspase activation, increased Bcl-2 expression, and rapidly initiated proliferation in vitro of CD8(+) T cells expressing CCR5 and multiple TCRBV subfamilies. Furthermore, IL-15 receptor alpha-chain messenger RNA levels were increased in peripheral blood mononuclear cells during PHI. These results suggest that CCR5(+)Ki-67(+)Bcl-2(dim) activated T cells generated during PHI traffic via blood to tissue sites, where the cells may survive and/or further proliferate under the local influence of IL-2 or IL-15. Understanding cytokine effects on CCR5(+) T cells will be important in understanding chronic HIV-1 replication and pathogenesis.
Adult↗
Prospective evaluation of the effects of antiretroviral therapy on body composition in HIV-1-infected men starting therapy.
OBJECTIVE: Little prospective data are published on the natural history of HIV-associated lipodystrophy (HIVLD) in individuals beginning their first antiretroviral regimen. To investigate this a study was designed to explore changes in body composition occurring with antiretroviral therapy. STUDY DESIGN: A non-randomized, prospective, exploratory study of 40, HIV-infected men, naive to treatment, beginning antiretroviral therapy. Regular assessments of body composition, and metabolic and immunological parameters were performed. RESULTS: Mean follow-up was 96 (SD 45) weeks of therapy. There were increases in limb fat, central abdominal fat and lean mass over the initial 24 weeks of therapy followed by a selective, progressive loss of limb fat from week 24. There was a median 13.6% [interquartile range (IQR), 0.9-26.3] loss of limb fat per year from week 24 onwards. Treatment with stavudine, higher baseline HIV RNA, higher baseline 'T' score and lower week 24 lean mass were associated with higher rate of limb fat loss from week 24. In multivariate analysis, treatment with stavudine was the strongest independent factor associated with rate of limb fat loss (P = 0.05). Hypercholesterolaemia developed early in treatment, whereas hypertriglyceridaemia, hyperinsulinaemia and decreased bone mineral density developed later. The largest changes in CD4 cell counts and HIV viral load, seen early into treatment, were associated with gain rather than loss of fat. CONCLUSIONS: This is the first prospective study demonstrating that treatment with antiretrovirals results in progressive, selective loss of limb fat. Loss of limb fat occurred after the period of most intense immune restoration, making an immune aetiology unlikely.
Adipose Tissue↗
Brief report: incubation and duration of specific symptoms at acute retroviral syndrome as independent predictors of progression to AIDS.
The incubation and duration of acute retroviral syndrome (ARS) have been associated with progression to AIDS. We assessed the independent effect of specific symptoms at ARS on the rate of progression to AIDS or a CD4+ count of <200 cells/mm3 in 70 ARS patients. The incubation and duration of ARS features were stratified on their medians. The Cox regression model was used to calculate the adjusted relative hazard (ARH) of progression. Short incubations of fever (ARH = 5.8, P = 0.004), fatigue (ARH = 2.7, P = 0.06), and myalgia (ARH = 3.8, P = 0.04) were associated with faster disease progression, as was the long duration of most symptoms (ARH range: 3.1-8.1, P < 0.03 to P < 0.001). Pathogenetic mechanisms involved in the incubation of ARS features may be associated with progression to AIDS.
Acute Disease↗
Pharmacokinetics of once-daily saquinavir hard-gelatin capsules and saquinavir soft-gelatin capsules boosted with ritonavir in HIV-1-infected subjects.
OBJECTIVE: To investigate the pharmacokinetics of once-daily saquinavir (SQV) hard-gelatin capsule (HGC)/ritonavir (RTV), 1600/100 mg, compared with once-daily SQV soft-gelatin capsule (SGC)/RTV, 1600/100 mg. METHODS: We evaluated 13 randomly selected HIV-1-infected subjects taking once-daily SQV SGC/RTV, 1600/100 mg, plus dual nucleoside reverse transcriptase inhibitors (NRTIs) in this pharmacokinetic (PK) substudy. Subjects took 1 week of SQV HGC/RTV and NRTIs, followed by steady-state SQV PK determinations. Subjects then changed to SQV SGC/RTV and NRTIs for 1 week, followed again by steady-state SQV PK determinations. Area under the plasma concentration versus time curve (AUC), maximum concentration (C(max)), minimum concentration (C(min)), time to C(max), and elimination half-life were calculated. RESULTS: There was no significant difference in AUC values between HGCs and SGCs, with a median (plus interquartile range [IQR]) of 50.0 (42.6-71.5) versus 35.5 (28.0-50.2) mg/L/h, respectively ( =.056). Intersubject variability resulted in 4 of 13 subjects on the SQV SGCs and 2 of 13 subjects on the SQV HGCs having a C(min) below the minimum effective concentration of 0.05 mg/L. CONCLUSION: Once-daily SQV HGCs, 1600 mg, boosted with once-daily RTV, 100 mg, resulted in PK parameters that were similar to those observed with 1600 mg of SQV SGC/100 mg RTV once daily. Once-daily SQV HGC/RTV, 1600/100 mg, may be easier to use in developing countries and may increase access where drug costs can be less, the capsule size is smaller, and the need for refrigeration is lessened.
Administration, Oral↗
No increase in protease resistance and a decrease in reverse transcriptase resistance mutations in primary HIV-1 infection: 1992-2001.
Rates of antiretroviral resistance in recently transmitted virus in Sydney, Australia fluctuated over the past decade, influenced by treatment trends. Current rates of drug resistance are not high in historical terms or compared with those reported. Rates of resistance to reverse transcriptase inhibitors peaked in the mid-1990s, fell dramatically with the introduction of combination therapy and appear to have plateaued at 10-15% over the past 3 years. Primary resistance mutations in the protease gene are still rare.
Acute Disease↗
Effector HIV-specific cytotoxic T-lymphocyte activity in long-term nonprogressors: associations with viral replication and progression.
Ex vivo effector cytotoxic T-lymphocyte (CTL) activity was assessed in 27 members of the Australian Long-Term Nonprogressor cohort and correlated with genetic, virological, and immunological markers. The 27 individuals were antiretroviral naive with CD4(+) T-cell counts of >500 cells/ microl for more than 8 years after human immunodeficiency virus type 1 (HIV-1) infection. Effector CTL activity was determined using a standard ex vivo chromium release assay. Individuals with CTL activity (HIV-1 env(IIIB) or pol or gag) were then compared to those without CTL activity in relation to plasma HIV-1 RNA, ICD p24 antigen, beta(2)-microglobulin, CD4 and CD8 T-cell counts, CCR5 and CCR2b genotypes, and progression to CD4 <500 cells/microl or commencement of antiretroviral treatment. Of the 27 individuals examined, 19 had no detectable effector CTL activity. The eight individuals with detectable CTL activity had significantly higher plasma levels of HIV-1 RNA (P = 0.014), immune complex dissociated p24 antigen (P = 0.006), and beta(2)-microglobulin (P = 0.009). There was increased risk of progression within 4 years of study entry in individuals with detectable effector CTL activity, higher plasma levels of HIV-1 RNA, higher beta(2)-microglobulin levels, and higher immune complex dissociated p24 antigen levels at enrollment (P = 0.017, P = 0.004, P = 0.027, P = 0.008 respectively). Multivariate analysis demonstrated viral load remained the strongest predictor of disease progression within this group (P = 0.017). There were no significant associations between CTL response and chemokine receptor genotype. These findings demonstrate the importance of HIV replication in generating an effector CTL response and show that effector CTL activity may be an early predictor of progression in people with long-term asymptomatic HIV infection.
Antigen-Antibody Complex↗
Latest update of tests and improvements to US Coast Guard viscous oil pumping system.
Over the past nine years, the US Coast Guard has incorporated the prevention through people (PTP) philosophy as a "human factors" approach to learn how maritime operations can be regulated safer and be more efficient by evaluating training, management policies, operational procedures, and establishing partnerships with the maritime industry. One of the key elements of applying a PTP approach is identifying and incorporating lessons learned from major marine casualties and pollution incidents. Since 1997, the US Coast Guard National Strike Force has responded to three major oil spills involving foreign freight vessels grounding, which included the removal of highly viscous oil using various lightering equipment and systems. An informal workgroup consisting of the US Coast Guard, US Navy Supervisor of Salvage (NAVSUPSALV), and various representatives from oil pollution clean-up companies met at the following facilities: the Chevron Asphalt Facility in Edmonds, WA (September 1999), the Oil and Hazardous Materials Simulated Environmental Test Tank (OHMSETT) testing facility in Leonardo, New Jersey (November 1999 and March 2000), the Alaska Clean Seas (ACS) warehouse annex in Prudhoe Bay, AK (October 2000), and Cenac Towing Company facility in Houma, LA (May 2002). The group shared ideas and techniques, and tested different pumps and hose lengths with viscous oil. It was during the early tests that the first quantitative results showed just how efficient lubricated transport of heavy oil product could be, and broadened the knowledge of such methods to the entire industry. Although this technology had existed for many years in the oil production and handling industry, its use had never been investigated in a laboratory setting with regard to salvage response lightering systems.
Accidents↗
Rates of transmission of antiretroviral drug resistant strains of HIV-1.
BACKGROUND: It is clear that transmission of drug resistant HIV-1 is possible and occurs regularly. However, there is a lack of clarity concerning the true rate of this transmission in a given population, the impact of combination therapies on this rate, and the contribution of transmitted resistant virus to treatment failure either in an individual or on a population basis. OBJECTIVES: To provide a review of our current understanding of rates of transmission of drug resistant HIV-1 in various populations and to report the results of a study conducted to determine this rate in Sydney, Australia in the years 1992-2000. STUDY DESIGN: A review of the literature combined with a prospective study of antiretroviral drug resistance in 130 individuals who were diagnosed with symptomatic primary infection at St. Vincent's Hospital, Sydney, Australia between 1992 and 2000. Sequencing of reverse transcriptase (RT) and protease (PR) was performed by the TruGene HIV-1 genotyping kit (Visible Genetics Inc.). RESULTS: The results found in the Sydney population contrast with much of the literature. The prevalence of mutations that conferred primary resistance to protease inhibitors (PIs) was only 0.8% at position V82I. Secondary mutations/polymorphisms were seen in the PR at position L10I/V, K20R, M36I, L63P, A71T/V, or V77I in 60%. L63P was the most frequently found mutation (46.3%). The incidence of protease-resistant strains of HIV in primary HIV-1 infection did not change after the introduction of PIs in 1996. The distribution of the most common resistance mutations in the RT was as follows; M41L (8.5%) and T215Y (8.5%) and K70R (4.8%). The frequency of mutations associated with NRTI resistance was significantly lower in the post 1995 samples (43.9 vs. 19.1%, P < 0.05). Moreover, both M41L and K70R, but not T215Y, occurred with significantly decreased frequency in the post 1995 samples. CONCLUSIONS: In contrast to other studies we found no increase in the rate of PR resistance and a decrease in the rate of RT resistance in recently transmitted virus over the period 1992-2000. The reasons for the differences between these results and those reported from elsewhere may relate to treatment regimens used in the transmitting population and may have implications for treatment policies in this country.
Anti-HIV Agents↗
Effect of therapeutic drug monitoring on outcome in antiretroviral experienced HIV-infected individuals.
BACKGROUND: The role of therapeutic drug monitoring (TDM) in the routine management of HIV-infected individuals is still unclear, largely due to a lack of basic data regarding specific drug concentrations and how they correlate with maximal effect and minimal toxicity within given populations. Nevertheless, it has a potentially important role to play in the management of HIV-infected patients, with the aim of limiting toxicity, optimising antiviral effect and decreasing virological failure and emergence of viral resistance. OBJECTIVES: To measure serum concentrations of specific antiretroviral drugs in individuals changing antiretroviral therapy and assess relationship to virological response. STUDY DESIGN: A prospective, non-randomised, 24-week study of 40 antiretroviral experienced HIV-infected patients. Subjects had failed their previous antiretroviral regimen and were beginning new regimens based on genotypic testing. Serum antiretroviral concentrations and virological response was measured after initiation of treatment. RESULTS: There was a significant correlation between higher concentrations of lopinavir and efavirenz and better virological outcome. This was not seen with amprenavir. CONCLUSIONS: Use of TDM in this setting helps predict virological response to therapy. Optimal use of TDM would require dose adjustment on the basis of a TDM level. Further research is necessary to enable this practice to become routine in the management of HIV-infected patients.
Adult↗
Greater reversal of CD4+ cell abnormalities and viral load reduction after initiation of antiretroviral therapy with zidovudine, lamivudine, and nelfinavir before complete HIV type 1 seroconversion.
In a prospective open-label study, 41 male subjects received nelfinavir, zidovudine, and lamivudine stratified as either: early stage (ES; negative/indeterminate Western blot; n = 19) or late stage (LS; positive Western blot; n = 22) primary HIV-1 infection. Despite higher median baseline HIV-1 RNA levels and lower CD4(+) cell numbers in the ES subjects, a significantly greater decline in viral load (-3.46 vs. -2.83 log(10) copies/ml; p = 0.023) and increase in CD4(+) cell number (+85 vs. +41 cells/month increase, p = 0.01) were observed over the first 3 months of therapy such that both groups had comparable results at 1 year. The proportion with HIV-1 RNA < 50 copies/mL at 1 year was similar (9 of 19 ES subjects and 11 of 22 LS subjects by intention-to-treat analysis). Memory CD4(+) cell numbers, and activated CD4(+) percentages, were also significantly improved in ES subjects. Despite poorer prognostic markers at baseline ES subjects achieved responses similar to those of LS subjects after 1 year of treatment.
Anti-HIV Agents↗