HIV Seropositivity: Gazzard B

Pozniak A, Gazzard B, Anderson J, Babiker A, Churchill D, Collins S, Fisher M, Johnson M, Khoo S, Leen C, Loveday C, Moyle G, Nelson M, Peter B, Phillips A, Pillay D, Wilkins E, Williams I, Youle M, Anonymous00074. · Chelsea and Westminster Hospital, London, UK. · HIV Med. · Pubmed #14511246 No free full text.

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Boffito M, Dickinson L, Hill A, Back D, Moyle G, Nelson M, Higgs C, Fletcher C, Mandalia S, Gazzard B, Pozniak A. · Chelsea and Westminster Hospital, London, UK. · Antivir Ther. · Pubmed #15259905 No free full text.

Abstract: OBJECTIVE: To evaluate the steady-state pharmacokinetics and safety of two once-daily saquinavir/ritonavir (SQV/RTV) regimens, 1600/100 and 2000/100 mg, in HIV-positive patients. METHODS: Eighteen HIV-infected adults treated with the standard twice-daily SQV/RTV 1000/100 mg regimen were enrolled in this open-label, two-phase, crossover pharmacokinetic study. The steady-state pharmacokinetics of SQV administered with 100 mg RTV were investigated following once-daily doses of 1600 mg or 2000 mg or a twice-daily dose of 1000 mg. Plasma drug concentrations were determined by high performance liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were calculated using a non-compartmental model. RESULTS: Compared with SQV 1000 mg twice daily, the Cmax of SQV following a 1600 mg and 2000 mg dose increased in a dose-proportional manner [geometric mean (95% CI) 1915 (1656-2850) ng/ml for 1000 mg, 2782 (2249-4330) ng/ml for 1600 mg and 4179 (3429-6105) ng/ml for 2000 mg doses, respectively]. SQV Ctrough values were 539 (453-1011), 106 (76-223) and 231 (75-822) ng/ml, respectively. A SQV Ctrough value greater than 100 ng/ml was achieved in all subjects on the twice-daily regimen, in 9/18 (50%) subjects on the 1600/100 mg once-daily regimen, and in 14/17 (82%) subjects on the 2000/100 mg once-daily regimen. The once-daily regimens were well tolerated, with mild-to-moderate gastrointestinal symptoms being the only events reported by a small number of patients. CONCLUSION: This is the first study to evaluate the pharmacokinetics of once-daily SQV/RTV 2000/100 mg in HIV-infected subjects. Our findings suggest that this regimen may be an alternative to twice-daily 1000/100 mg doses and should be further evaluated in efficacy studies. The data indicate that most patients (14/17) on once-daily 2000/100 mg achieve trough concentrations above target values (determined for HIV wild-type) for efficacy of SQV with the use of just 100 mg RTV/day and with good tolerability.

Pires A, Hardy G, Gazzard B, Gotch F, Imami N. · Department of Immunology, Imperial College London, UK. · J Acquir Immune Defic Syndr. · Pubmed #15213561 No free full text.

Abstract: To measure proviral HIV-1 DNA in patients treated with effective antiretroviral therapy (ART) during recent and chronic HIV-1 infection, and in long-term non-progressors (LTNP). We quantified HIV-1 DNA in peripheral blood samples from 39 HIV-1-infected subjects; 26 patients initiated non-nucleoside reverse transcriptase inhibitor (NNRTI) based ART at two different stages of infection: 16 during recent infection (RI) (HIV-1 exposure >60 days <1 year), and 10 during chronic infection (CI) (infected >2 years). The results were compared with those seen in 13 LTNP (infected >8 years, therapy naïve, and controlled viremia). Thirty-six weeks after initiation of ART, HIV-1-proviral DNA levels decreased from baseline in the RI group (P < 0.005) to levels comparable to LTNP. HIV-1 DNA also declined in the CI group (P = 0.053) but it remained significantly higher than in RI (P < 0.002) and LTNP (P < 0.02). However, plasma HIV-1 RNA levels become undetectable in 80% of CI patients 12 weeks post initiation of ART, compared to 41.2% in the RI group. All patients reached undetectable viremia by week 36 of therapy. These data indicate that initiation of NNRTI based ART during recent HIV-1 infection reduces HIV-1 DNA to levels comparable to those seen in LTNP, which is not apparent if therapy is started during chronic infection, and suggests an association between timing of initiation of ART and decay of the HIV-1 reservoir.

Easterbrook PJ, Yu LM, Goetghebeur E, Boag F, McLean K, Gazzard B. · Department of HIV and Genitourinary Medicine, Chelsea and Westminster Hospital, London, UK. · AIDS. · Pubmed #10780719 No free full text.

Abstract: OBJECTIVE: To examine temporal trends (1986-1996) in the CD4 cell count at first HIV-1 positive test and initial AIDS diagnosis, and the influence of selected patient characteristics and treatment factors on these trends. DESIGN: A retrospective clinic-based study. SETTING: Three hospital-based clinics in West London. PATIENTS: A group of 5921 adult HIV-1-seropositive persons and 2835 reported patients with AIDS over a 10-year period from 1 January 1986 to 1 October 1996. METHODS: The CD4 cell count at HIV diagnosis (CD4HIV) was defined as the nearest CD4 cell count to within 2 months of HIV diagnosis; and the CD4 cell count at AIDS diagnosis (CD4AIDS) as the last CD4 cell count in the two months prior to the development of AIDS. Simple and multiple linear regression analysis were used to examine the influence of selected covariates on CD4HIV and CD4AIDS. RESULTS: The percentage of patients with an available CD4HIV and CD4AIDS increased from less than 5% in 1987 to 53% and 40%, respectively, in 1990, and 79% and 48%, respectively, in 1996. Patients with a missing CD4HIV or CD4AIDS were younger and less likely to have received antiretroviral therapy or prophylaxis for Pneumocystis carinii pneumonia (PCP). There was no significant change in CD4HIV over a 10-year period (median 334 x 10(6) cells/l), but a lower CD4HIV was associated with older age at presentation and injecting drug use. There was a delay in the onset of clinical AIDS, with a fall in the median CD4AIDS value from 99 x 10(6) cells/l prior to 1987, to 58 x 10(6) cells/l in 1990, 68 x 10(6) cells/l in 1994 and 60 x 10(6) cells/l in 1996; this decline in onset was seen for PCP as well as for cytomegalovirus and atypical mycobacterial infections. At all time periods, a lower CD4AIDS was associated with combined use of antiretroviral therapy and PCP prophylaxis. After adjustment for use of antiretroviral therapy and PCP prophylaxis prior to AIDS diagnosis, year of diagnosis was no longer associated with CD4AIDS. There was a significant trend towards an improved survival following AIDS diagnosis from 20.1 months prior to 1988, to 20.3 months (1989-1990), 21.0 months (1991-1992) and 22.1 (1993-1994) (P < 0.0005). CONCLUSIONS: The observed decline in CD4AIDS value was related to the introduction of antiretroviral therapy in 1988, and PCP prophylaxis in 1989. Temporal changes in the CD4 cell count at HIV and AIDS diagnosis among different demographic groups can provide insights into the changing natural history of the HIV epidemic and access to medical care. We recommend monitoring of the CD4 cell count at new HIV and AIDS diagnosis and at initiation of antiretroviral therapy as additional measures in national HIV/AIDS surveillance.