Combined therapy with saquinavir, ritonavir and stavudine in moderately to severely immunosuppressed HIV-infected protease inhibitor-naive patients

¹ Basel Centre for HIV Research, Outpatient Department of Internal Medicine, University Hospital Basel, ² Department of Internal Medicine, Cantonal Hospital St Gallen, ³ Department of Internal Medicine, Regional Hospital Lugano, ⁴ Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, ⁵ Basel Centre for HIV Research, Institute for Medical Microbiology, University Basel, ⁶ Division of Infectious Diseases, University Hospital Bern, ⁷ Division of Infectious Diseases, University Hospital Lausanne, ⁸ Roche Pharma AG, Reinach, and ⁹ Division of Infectious Diseases, University Hospital Geneva, Switzerland Objective To assess the short‐term and long‐term effect of a combination of saquinavir, ritonavir and stavudine in moderately to severely immunosuppressed protease inhibitor‐naive patients. Design Prospective open‐label multicentre study. Patients and Methods A total of 64 protease inhibitor‐naive and stavudine‐naive HIV‐infected patients with a CD4 count of < 250 cells/μL and > 10 000 HIV‐1 RNA copies/mL received saquinavir hard‐gelatin capsules, ritonavir and stavudine. Full (drop in viraemia of > 2 log₁₀ and/or < 500 copies/mL) and partial responders (drop to between 500 and 5000 viraemia copies/mL) at week 9 (end of phase I) entered the second phase (additional 12‐month period). Results Fifty‐six patients completed phase I, 45 (70%) full responders and nine (14%) partial responders by intent‐to‐treat analysis. Thirty‐nine patients completed phase II, 33 (52%) full responders and two (3%) partial responders. Six patients had < 50 HIV‐1 RNA copies/mL at week 9, and 20 (31%) patients at month 12 of phase II. Mean CD4 cell counts increased significantly in the 56 patients from 89 to 184 cells/μL after 9 weeks and from 100 to 292 cells/μL in the 39 patients treated for another 12 months. Higher baseline viraemia and lower baseline CD4 cell counts were not associated with an unfavourable virological response at week 9 and month 12 of phase II. HIV DNA in peripheral blood monocytes decreased substantially (? 1.5 log₁₀) but was detectable in all except one patient at the end of phase II. Conclusion In protease‐ and stavudine‐naive HIV‐infected patients with moderate to severe immunosuppression, saquinavir in combination with ritonavir and stavudine caused a substantial long‐term decrease in plasma viral load in approximately half the participants and a substantial increase in CD4 cell counts.     

Decreased exposure to saquinavir in HIV-1-infected patients after long-term antiretroviral therapy including ritonavir and saquinavir

OBJECTIVE: To explore whether steady-state plasma pharmacokinetics of ritonavir and saquinavir change during long-term treatment in HIV-1-infected patients on antiretroviral treatment including ritonavir and saquinavir. METHODS: The pharmacokinetics of ritonavir and saquinavir were assessed during an 8-h period on two occasions in six HIV-1 infected patients on stable twice daily treatment with ritonavir 400 mg, saquinavir 400 mg and stavudine 40 mg with or without lamivudine 150 mg twice daily. RESULTS: The first study day was 4-12 months (median 7 months) after the start of the current regimen. The second study day was 9-15 months (median 10 months) later. No significant differences were observed for the ritonavir pharmacokinetics between the first and second study day. However, median change in plasma trough level of saquinavir between the two study days was -30% (range -79 to +11%; P = 0.06). Median change in maximum plasma concentration was -40% (range -62 to +34%; P = 0.09). The median change in area under the plasma concentration versus time curve over 0-8 h was -33% (range -53 to +21%; P = 0.06). CONCLUSION: The exposure to saquinavir decreased over time in HIV-infected patients on stable antiretroviral therapy. These data suggest that regular monitoring of plasma drug concentrations should become part of routine patient care even in apparently compliant patients.     

SOLO: 48-week efficacy and safety comparison of once-daily fosamprenavir /ritonavir versus twice-daily nelfinavir in naive HIV-1-infected patients

OBJECTIVE: To compare the magnitude and durability of the antiviral response to fosamprenavir (FPV) plus ritonavir (RTV) once-daily (FPV/r QD) with nelfinavir twice-daily (NFV BID), each administered with abacavir and lamivudine twice-daily. METHODS: An international, phase III, randomized, open-label study in antiretroviral therapy-naive, HIV-infected adults. RESULTS: Patients with advanced HIV disease received FPV/r QD (n = 322) or NFV BID (n = 327). At week 48, 69% of patients in the FPV/r QD group and 68% in the NFV BID group had plasma HIV-1 RNA (vRNA) < 400 copies/ml, whereas 55% of patients in the FPV/r QD group and 53% in the NFV BID group had vRNA < 50 copies/ml (intent to treat, rebound/discontinuation = failure). More patients in the NFV BID group (17%) experienced virological failure than in the FPV/r QD group (7%). Efficacy of FPV/r QD was maintained in patients with CD4+ cell counts < 50 x 10 cells/l or vRNA >/= 100 000 copies/ml at entry. At week 48, median CD4+ cell counts were increased to 203 x 10 cells/l (FPV/r QD group) and 207 x 10 cells/l (NFV BID group). Both regimens were generally well tolerated. Diarrhea was more common on NFV BID than on FPV/r QD (16 versus 9%; P = 0.008). Fasting lipid profile results were generally favorable in both treatment arms. FPV/r QD maintained plasma amprenavir (APV) trough concentrations above the mean phenotypic drug-susceptibility (IC50) for wild-type virus for APV. CONCLUSION: As a first choice protease inhibitor with a low daily pill burden, FPV/r QD was well tolerated and provided potent, durable antiviral suppression.     

Pharmacokinetic and tolerability profile of twice-daily saquinavir hard gelatin capsules and saquinavir soft gelatin capsules boosted with ritonavir in healthy volunteers

Objective

To evaluate the pharmacokinetics and safety of a boosted saquinavir (SQV)/ritonavir (RTV) combination, administered as either the hard gelatin capsule (HGC) or soft gelatin capsule (SGC) formulation of SQV, in 24 healthy volunteers.

Methods

This was a single‐centre, open‐label, randomized, 2 × 2 crossover study. Twelve subjects were randomized to receive SQV/RTV 1000 mg/100 mg twice daily (BID) orally for 10 days, as either the HGC or SGC formulation. The pharmacokinetic profile of SQV was determined on day 10. Subjects then crossed over to the opposite SQV formulation, and the pharmacokinetic profile was determined again on day 20. The primary analysis was the assessment of bioequivalence based on logarithmically transformed values for AUC_{(0?24 h)} and C_max for the two formulations.

Results

There was a statistically significant increase in the geometric means of all the pharmacokinetic variables evaluated for SQV‐HGC/RTV compared with SQV‐SGC/RTV. A mean AUC_{0?24 h}‐value of 15.798 µg/mL/h was reported for the HGC formulation compared with 11.655 µg/mL/h for the SGC formulation (P = 0.0043). The SQV‐HGC/RTV combination was better tolerated in terms of gastrointestinal system disorders. Furthermore, no elevations in triglycerides or total cholesterol were reported with SQV/RTV during the entire study period.

Conclusion

In healthy volunteers, RTV boosting of SQV‐HGC produces plasma exposures at least comparable to SQV‐SGC, which is accompanied by an improvement in gastrointestinal system disorders.

     

Virological and immunological profiles among patients with undetectable viral load followed prospectively for 24 months

Objective

To quantify HIV‐RNA in plasma, in lymphoid tissue and proviral DNA in peripheral blood mononuclear cells and to relate these to immunological markers among patients with plasma viral load counts of ≤ 200 HIV‐RNA copies/mL.

Methods

A prospective study of one hundred and three patients was undertaken with an inclusion criteria of plasma viral load of ≤ 200 copies/mL. The patients had advanced HIV infection; 25% had developed AIDS. Patients were seen every 6 months for a period of 2 years.

Results

The median plasma viral load was < 20 copies/mL with no increase during follow‐up. Thirty‐one per cent had plasma viral load of ≤ 20 copies/mL at all visits, 44% had ≥ 1 measurement with 21–200 and 25% had ≥ 1 sample with plasma HIV‐RNA > 200 copies/mL. Lymphoid tissue viral load was low at enrolment and declined further during follow‐up. Baseline HIV‐DNA and immunoglobulin (IgA) differed significantly between the plasma viral load rebound groups (P < 0.05).

Conclusion

In this cohort, selected solely on the basis of having a plasma viral load of ≤ 200 copies/mL, we found stable or declining viral loads in the measured compartments during 2 years of follow‐up. Baseline HIV‐DNA and IgA levels were higher among patients with less complete virological suppression relative to patients with persistently undetectable plasma HIV‐RNA. Hence, a high cellular level of HIV‐DNA and high plasma IgA may predict subsequent development of low‐grade viraemia.

     

COVID-19 pneumonia in an HIV-positive woman on antiretroviral therapy and undetectable viral load in Porto Alegre,Brazil

COVID-19 pandemic has been a problem worldwide. It is important to identify people at risk of progressing to severe complications and to investigate if some existing antivirals could have any action against SARS-CoV-2. In this context, HIV-infected individuals and antiretroviral drugs might be included, respectively. Herein we present the case of a 63-year-old HIV-infected woman with undetectable viral load, on dolutegravir, tenofovir and lamivudine, who was hospitalized due to COVID-19 pneumonia. In spite of having some clinical markers of severity on admission, the patient improved and was discharged after a week. To our knowledge, this is the first report of severe SARS-CoV-2 infection in an HIV-infected individual in Brazil.     

Evaluation of the impact of highly active antiretroviral therapy on immune recovery in antiretroviral naive patients

Objectives To examine the extent of immune reconstitution in treatment‐naive patients with CD4 T‐cell counts <500 cells/μL following 48 weeks of highly active antiretroviral therapy (HAART). Methods Thirteen antiretroviral naive patients were evaluated longitudinally for 48 weeks on HAART utilizing immune functional and lymphocyte phenotyping assays, including lymphocyte proliferation assay, flow cytometric evaluation of cell surface markers, and delayed type hypersensitivity skin tests. Virologic responses were monitored using commercially available viral load assays and gag/pol mRNA quantification using simultaneous immunophenotyping/UltraSensitive fluorescence in situ hybridization (ViroTect In Cell HIV‐1 Detection Kit; Invirion, Frankfort, MI). Thymic function was evaluated for a subset of four patients using real‐time polymerase chain reaction (PCR) for T‐cell receptor excision circle (TREC) quantification and thymic scans using computerized axial tomography (CT) of the thymus. Results HAART initiation resulted in a significant decline in plasma viremia and percentage of infected peripheral blood cells, and a rise in CD4 T cells from a baseline median of 207 cells/μL to a week‐48 median of 617 cells/μL. The rise was predominately in CD4 memory cells. Naive T cells also increased in number, but at a slower rate. Activated (HLA‐DR CD38) CD4 and CD8 T cells were elevated at baseline (24 and 62%, respectively) and declined by week 48 (17 and 36%, respectively) but did not reach normal levels. The number of Fas CD4 T cells increased from a baseline median of 169 to 381 cells/μL at week 48. Both soluble interleukin (IL)‐2 and tumour necrosis factor (TNF) II receptors declined by week 48. HIV p24 lymphocyte proliferation assay responses were transiently detected in three patients. TREC values increased from a median 6400 copies/μg at baseline to a week‐48 median value of 26 697 copies/μg. Conclusion Immune functional reconstitution was not achieved in these HAART naive patients.     

佳息患联合施多宁治疗HIV感染者/AIDS患者6个月效果及耐药性初步观察

目的探讨规范化应用蛋白酶抑制剂茚地那韦(Indinavir,佳息患)联合非核苷类逆转录酶抑制剂依非韦仑(Efavirenz,施多宁)治疗艾滋病病毒(HIV)感染者/AIDS患者的疗效和耐药情况。方法用施多宁联合佳息患对10例HIV感染者/AIDS患者进行为期6个月的治疗,于治疗前,治疗第1、3、6个月随访,监测病毒学和免疫学参数[病毒载量(VL)、CD4+细胞绝对计数、CD4+和CD8+免疫活化标志HLA-DR、CD3+8],药物毒副作用,基因型耐药变异情况,临床表现和依从性。结果10例HIV感染者/AIDS患者治疗前平均VL为5.17log拷贝/ml(3.58×105拷贝/ml),治疗6个月后平均下降3.25log拷贝/ml(P<0.001),其中9例达到检测不出的水平(<400拷贝/ml)。CD4+T细胞绝对计数平均上升178个/μl(P<0.001)。CD3+8HLA-DR+CD4+细胞平均百分比和CD3+8HLA-DR+CD8+细胞平均百分比分别降低了14.9%(P<0.01)和22.9%(P<0.001)。病人临床症状缓解且耐受性良好,无严重不良反应发生。10例患者在治疗前和治疗6个月后均未出现原发耐药变异。结论佳息患联合施多宁规范化治疗不同感染阶段的中国HIV感染者/AIDS患者6个月,可有效抑制HIV-1复制,促进机体免疫重建,改善临床症状,提高生活质量,副作用在可接受范围内,无原发耐药变异发生。