Vitamin A supplementation and genital shedding of herpes simplex virus among HIV-1-infected women: a randomized clinical trial

Cross-sectional analyses have associated vitamin A deficiency with genital shedding of herpes simplex virus (HSV) among human immunodeficiency virus type 1 (HIV-1)-infected women. A randomized clinical trial of vitamin A supplementation given daily for 6 weeks was conducted among 376 women in Mombasa, Kenya, who were coinfected with HSV-2 and HIV-1. At follow-up, there was no significant difference in the detection of genital HSV DNA between women receiving vitamin A supplementation and women receiving placebo (40% vs. 44%, respectively; P = .5) Among women shedding HSV, there was no significant difference in the mean HSV DNA quantity between the group that received vitamin A supplementation and the group that received placebo (4.51 vs. 4.67 log10 copies/swab; P = .6). HSV shedding was associated with significantly higher vaginal and cervical HIV-1 shedding, even after controlling for the plasma HIV-1 load and the CD4 count. Vitamin A supplementation is unlikely to decrease HSV shedding and infectivity.     

泛昔洛韦单日疗法治疗复发性生殖器疱疹的临床对照研究

目的探讨泛昔洛韦单日疗法治疗复发性生殖器疱疹的疗效及安全性。方法采用随机、对照临床实验,比较泛昔洛韦单日疗法(1 000mg,2次/日,共1日)与传统的阿昔洛韦五日疗法(400mg,3次/日,共5日)的疗效及安全性。结果 136例复发性生殖器疱疹患者参加试验。试验组与对照组疗效比较,皮损愈合时间、症状消退时间、总病愈时间分别为(4.00±0.63)天vs.(3.85±0.90)天(t=1.13,P=0.26),(3.32±0.55)天vs.(3.18±0.77)天(t=1.22,P=0.22),(4.53±0.65)天vs.(4.45±0.95)天(t=0.57,P=0.57)。皮损顿挫比率分别为32.4%vs.26.8%(χ2=0.58,P=0.31),差异均无统计学意义。两种治疗方案不良反应发生率相近(28.0%vs.19.1%)(χ2=0.91,P=0.34),表现以头痛为主。结论泛昔洛韦单日疗法治疗复发性生殖器疱疹有效、安全,运用方便。     

Effects of interleukin-2 therapy combined with highly active antiretroviral therapy on immune restoration in HIV-1 infection: a randomized controlled trial

BACKGROUND: Intermittent interleukin-2 (IL-2) therapy leads to a sustained increase of CD4 T cells in HIV-1-infected patients. METHODS: Symptom-free HIV-1-infected patients who were naive to all antiretroviral drugs (n = 68) and/or to protease inhibitors (n = 50) and had a CD4 cell count of 200-550 x 10(6) cells/l were randomly assigned to start lamivudine/stavudine/indinavir alone (controls) or combined from week 4 with subcutaneous IL-2 (5 x 10(6) IU twice daily for 5 days: every 4 weeks for three cycles, then every 8 weeks for seven cycles). Immunological and virological results were monitored until week 74. RESULTS: CD4 T cell counts increased more in the IL-2 group than in the controls (median increases 865 and 262 x 10(6) cells/l, respectively; P < 0.0001); an 80% increase in CD4 T cells was achieving by 89% of the IL-2 group and by 47% of the controls (P < 0.0001). Decrease of plasma viral loads was similar in both groups. Compared with controls, IL-2 induced a greater increase of naive and memory CD4 T cells, lymphocyte expression of CD28 and CD25 (P < 0.0001) and natural killer cells (P < 0.001). In a logistic regression analysis, odds of being responders to recall antigens was 8.5-fold higher in IL-2 recipients (P = 0.002) than in controls. The former experienced a higher level of antibody response to tetanus vaccination at week 64 than controls (32 and 8 haemagglutinating units/ml, respectively; P = 0.01). CONCLUSIONS: The combination of antiviral drugs and IL-2 induced a greater expansion and function of CD4 T cells than antiretroviral drugs alone.     

Directly observed antiretroviral therapy to reduce genital tract and plasma HIV-1 RNA in women with poor adherence

Six women with substance abuse and poor adherence histories received daily antiretroviral directly observed therapy (DOT). Cervicovaginal lavage (CVL) and plasma HIV-1-RNA levels were measured at baseline, 1 month, 3 months, and 6 months. All subjects had undetectable (below 2.6 log10 copies/ml) CVL HIV-1-RNA levels by 3 months and undetectable plasma HIV-1-RNA levels by 6 months. The mean CD4 cell increase was 76 cells/mm3. DOT appears effective and may reduce infectiousness in this high-risk population.     

Slower decline of plasma HIV-1 RNA following highly suppressive antiretroviral therapy in primary compared with chronic infection

OBJECTIVES: To study the effect of highly suppressive antiretroviral therapy on the slopes of HIV-1 RNA decline in primary compared with chronic HIV-1 infection. METHODS: Slopes of HIV-1 RNA decline in plasma were compared before and after the start of highly suppressive antiretroviral therapy from five acutely infected patients who started treatment 2 to 5 weeks following the onset of clinical symptoms. Slopes of decline after the initiation of therapy were also compared with those found in 12 chronically infected individuals on the same therapy. Numbers and percentages of activated CD4 and CD8 T cells at baseline were compared as well. RESULTS: The pre-treatment slopes of HIV-1 RNA decline in the acutely infected individuals increased significantly (P = 0.0001) after the start of anti-retroviral therapy. However, these post-treatment slopes were lower than those found in the chronically infected individuals (P= 0.012). Slopes were inversely correlated (P= 0.012) with baseline HIV-1 RNA. Although the number of CD38+HLA-DR+ CD4 cells was higher in primary infection (P= 0.02), the percentage did not differ between primary and chronic infection. CONCLUSIONS: These findings indicate that antiretroviral therapy contributes significantly to the clearance of HIV-1 during primary infection. Based on the mathematical model the less steep RNA slope following the start of treatment in primary infection can be predicted to be the result of lower clearance of productively infected cells and higher burst size per cell per unit time. This may indicate a growing immune response to HIV-1 in this very early stage of infection.     

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.     

Cyclosporin A provides no sustained immunologic benefit to persons with chronic HIV-1 infection starting suppressive antiretroviral therapy: results of a randomized, controlled trial of the AIDS Clinical Trials Group A5138

BACKGROUND: Although the determinants of immune deficiency and immune restoration in chronic human immunodeficiency virus (HIV)-1 infection are not well understood, immune activation has been proposed as being central to the pathogenesis of HIV. METHODS: A randomized, controlled trial of cyclosporin A treatment for 2 weeks was performed in persons with chronic HIV-1 infection who were beginning a standardized antiretroviral therapy (ART) regimen. RESULTS: Treatment with cyclosporin A provided only a marginal and transient enhancement in circulating T cell restoration that was largely restricted to cells expressing the CCR7 chemokine receptor and that did not persist beyond 2 weeks. CONCLUSIONS: Cyclosporin A coadministered for 2 weeks with ART provided no sustained immunologic benefit to persons with chronic HIV-1 infection. If immune activation drives progressive immune deficiency in chronic HIV-1 infection, these activation pathways may not be sensitive to cyclosporin.     

Quantitative molecular monitoring of HIV-1 RNA during antiretroviral therapy

Summary Plasma HIV-1 RNA testing was used to monitor 43 HIV-1 infected patients newly placed on antiretroviral therapy or whose therapy had been recently changed. A polymerase chain reaction kit was used to measure HIV-1 RNA in clinical samples or frozen plasma. The cutoff of this test was 200 RNA copies/ml. The first group (11 patients) was stable on long-term zidovudine monotherapy when switched to stavudine. The HIV-1 RNA of three patients who had a regular decline in CD4⁺ T cell count did not change despite this switch, with a mean follow-up of 630 days. The HIV-1 RNA copy numbers of eight patients whose CD4⁺ T cell counts were stable declined an average of 0.53 log₁₀ between days 90 and 650. The second group (14 patients) was on long-term zidovudine monotherapy and had declining CD4⁺ T cell counts over the past 6 months. Lamivudine was added to this regimen on day 0. HIV-1 RNA copy number decreased rapidly within 30 d, reaching –0.86 log₁₀ on day 90, and this effect was maintained thereafter, with a mean follow-up of 161 days. There was a concomitant mean gain of +33 CD4⁺ T cells on day 90. The third group (nine patients) had never received anti-retroviral therapy and was given zidovudine + didanosine. HIV-1 RNA copy number decreased in all cases but one, reaching –1.31 log₁₀ on day 150. This decrease was transient in three cases. The last group (nine patients) had also not had previous anti-retroviral therapy and was given zidovudine + didanosine + lamivudine in combination. HIV-1 RNA copy numbers declined rapidly in all cases, to below the cutoff in eight cases within a mean period of 50.5 days. The CD4⁺ cell counts increased by 164 cells/µl on day 14 and by 201 cells/µl on day 180. The response to therapy of the total population of 43 patients varied according to cases. The relative changes in p24 antigen compared to HIV-1 RNA also differed between patients. Measurement of HIV-1 viremia appears to be a valuable tool in current practice for individualizing therapy.

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Quantitatives molekulares Monitoring der HIV-1 RNA unter Behandlung mit anti-retroviralen Substanzen

Zusammenfassung 43 HIV-1 infizierte Patienten, die erstmals auf eine anti-retrovirale Therapie eingestellt oder deren Behandlung umgestellt wurde, wurden einem Monitoring hinsichtlich der HIV-1 RNA im Plasma unterzogen. Zur quantitativen Bestimmung der HIV-1 RNA in klinischen Proben oder eingefrorenem Plasma wurde ein Polymerasekettenreaktions(PCR)-Kit verwendet. Die Nachweisgrenze dieses Tests lag bei 200 RNA-Kopien/ml. Die erste Gruppe von 11 Patienten war auf eine Langzeit-Zidovudin-Monotherapie eingestellt und wurde auf Stavudin umgestellt. Trotz der Therapieänderung nahm die HIV-1 RNA-Menge bei drei Patienten mit sinkenden CD4⁺ T-Zell-Zahlen bei einer Verlaufszeit von 630 Tagen nicht ab. Die acht Patienten mit stabilen CD4⁺ T-Zell-Zahlen ließen im Mittel eine Abnahme der HIV-1 RNA-Kopien um 0,53 Log₁₀ zwischen Behandlungstag 90 und 650 erkennen. Die 2. Gruppe von 14 Patienten hatte eine Langzeitbehandlung mit Zidovudin in Monotherapie erhalten, die CD4⁺-T-Zell-Zahlen nahmen in den vergangenen 6 Monaten ab. Sie erhielten zusätzlich Lamivudin vom Tag 0 an. Innerhalb 30 Tagen trat eine rasche Reduktion der HIV-1 RNA-Kopien ein, am Tag 90 betrug die Abnahme 0,86 Log₁₀. Der Effekt blieb über eine mittlere Verlaufsbeobachtungszeit von 161 Tagen erhalten. Zugleich hatten am Tag 90 die CD4⁺ T-Zellen um 33/µl zugenommen. In einer dritten Gruppe wurden neun Patienten erstmals auf eine antiretrovirale Therapie eingestellt. In allen Fällen nahm die Zahl der HIV-1 RNA-Kopien rasch ab, in acht Fällen unter den Grenzwert bei mittlerer Behandlungszeit von 50,5 Tagen. Die CD4⁺ T-Zellen erhöhten sich um 164/µl am Tag 180. Die gesamte Patientengruppe zeigte ein individuell stark variierendes Therapieansprechen. Im p24 Antigen-Spiegel-Verhalten waren verglichen mit den HIV-1 RNA-Werten ebenfalls Unterschiede zu finden. Die Bestimmung der HIV-1 Virämie erwies sich als wertvolle Methode für die individuelle Therapieeinstellung.

     

Herpes simplex virus (HSV)-suppressive therapy decreases plasma and genital HIV-1 levels in HSV-2/HIV-1 coinfected women: a randomized, placebo-controlled, cross-over trial

A randomized cross-over trial of herpes simplex virus type 2 (HSV-2)-suppressive therapy (valacyclovir, 500 mg twice daily, or placebo for 8 weeks, a 2-week washout period, then the alternative therapy for 8 weeks) was conducted among 20 Peruvian women coinfected with HSV-2 and human immunodeficiency virus type 1 (HIV-1) who were not on antiretroviral therapy. Plasma samples (obtained weekly) and endocervical swab specimens (obtained thrice weekly) were collected for HIV-1 RNA polymerase chain reaction. Plasma HIV-1 level was significantly lower during the valacyclovir arm, compared with the placebo arm (-0.26 log10 copies/mL, a 45% decrease [P < .001]), as was cervical HIV-1 level (-0.35 log10 copies/swab, a 55% decrease [P < .001]). Suppressive HSV-2 therapy has the potential to reduce HIV-1 infectiousness and slow HIV-1 disease progression.     

Frequent reactivation of herpes simplex virus among HIV-1-infected patients treated with highly active antiretroviral therapy

The effect of highly active antiretroviral therapy (HAART) on control of herpes simplex virus (HSV) in human immunodeficiency virus (HIV) type 1-infected subjects is not known. Among 28 HAART-treated and 49 untreated subjects with HIV-1 and HSV-2 infections, mucosal HSV shedding (median, 18% and 29% of days positive for HSV DNA, respectively; P=.08) and HSV DNA level (median, 56,250 and 50,000 copies/mL, respectively; P=.20) were similar. Treated subjects reported significantly fewer days with HSV lesions, compared with untreated subjects (2.8% vs. 11.3% of days, respectively; P=.001). Thus, mucosal HSV shedding and HSV-2 reactivation were still frequent among treated subjects, even though HAART was associated with fewer days with HSV lesions.     

Complications after caesarean section in HIV-1-infected women not taking antiretroviral treatment

HIV-1-infected women have a considerably increased risk of postoperative morbidity after caesarean sections. We showed that this risk was independent of current antiretroviral therapy.     

Rate of HIV-1 RNA rebound upon stopping antiretroviral therapy.

OBJECTIVE: To determine the rate of plasma HIV-1 RNA rebound in patients stopping highly active antiretroviral therapy (HAART) after achieving undetectable viral load. DESIGN: Sequential plasma HIV RNA levels were measured in six patients during the 21 days following withdrawal from HAART. METHODS: Plasma samples were obtained from six patients who chose to withdraw from HAART because of lipodystrophy, narcotic overdose, insomnia and/or high blood pressure. Longitudinal plasma viral load was determined in triplicate upon stopping therapy. RESULTS: All patients had plasma viral loads below 50 HIV RNA copies/ml at the time of stopping therapy and had had levels below 500 copies/ml for a median of 390 days (range 39-542 days). Plasma HIV rebound upon stopping therapy was rapid (median increase 0.2 log/day; range 0.15-0.42 log/day) and initially appeared to follow first-order kinetics. Plasma HIV RNA levels returned to greater than 500 copies/ml within 6 to 15 days (median 10 days) and approached or exceeded pre-therapy levels in all patients within 21 days of stopping therapy. Extrapolating backwards to the time at which individuals stopped therapy suggested that patients had tens of thousands of total body plasma HIV RNA copies despite having 'undetectable' plasma HIV RNA. CONCLUSIONS: HIV RNA in plasma rebounds within days of stopping antiretroviral therapy. A considerable burden of total body plasma HIV RNA likely remains even during effective HAART therapy.     

Cognitive-behavioral intervention to enhance adherence to antiretroviral therapy: a randomized controlled trial (CCTG 578)

OBJECTIVE: We conducted a randomized, multi-site, controlled trial of a cognitive-behavioral adherence intervention for patients initiating or changing an antiretroviral (ART) regimen. DESIGN: A 3 x 2 factorial design was used with the primary randomization assigning patients (1: 1: 1) to one of two adherence interventions or usual care. METHODS: The five-session adherence interventions consisted of cognitive-behavioral and motivational components, with or without a 2-week pre-treatment placebo practice trial. Intent-to-treat analysis used probability weights and regression tree analysis to account for missing data. RESULTS: A total of 230 patients were randomized; 199 started ART, of whom 74% completed the 48-week study. Electronic monitored adherence outcomes between the two intervention groups did not differ significantly and were thus pooled in analyses. At week 4, 82% of intervention patients had taken at least 90% of their prescribed ART doses, compared with 65% of controls (P < 0.01); this group difference dropped to 12% at week 12 (72 versus 60%; P = 0.15) and 11% at week 24 (66 versus 55%; P = 0.28). Mean adherence in the intervention group was significantly higher than the control group at week 24 (89 versus 81%; P < 0.05) only. There were no group differences with respect to HIV-1 RNA throughout the study. CONCLUSIONS: The effects of the cognitive-behavioral intervention on adherence were modest and transient, and no effects were observed on viral load or CD4 cell count. More robust effects may require a more intense intervention that combines ongoing adherence monitoring and individualized intervention "dosage" that matches the need and performance of each patient.