Clinical experience with nevirapine combined with tenofovir plus emtricitabine or lamivudine-containing regimens in HIV-infected subjects

We retrospectively evaluated the durability and reasons for discontinuation of nevirapine (NVP) in combination with a tenofovir (TDF) and emtricitabine (FTC) or lamivudine (3TC)-containing antiretroviral therapy (ART) regimen in an Australian outpatient setting. Between January 2003 and June 2009, 64 patients (29 na?ve and 35 treatment-experienced) received NVP/TDF-based regimens. The median exposure was 13.0 months (interquartile range [IQR] 6.0-20.0 months). The two- and three-year probability of continuing a NVP/TDF with FTC or 3TC regimen was 76% and 70%, respectively. Thirteen (20.3%) patients discontinued their regimen during the observation period. Reasons for discontinuation included virological failure in four (6.3%), rash in three (4.7%), lost to follow-up in three (4.7%), liver toxicity in two (3.1%) and HIV-1-related encephalopathy in one (1.6%). Long-term follow-up with a NVP/TDF-based regimen showed a low rate of discontinuation and enabled physicians to extend the use of ART over a long period, often with simplified (once-daily) regimens.     

Switch from a first virologically effective protease inhibitor-containing regimen to a regimen containing efavirenz, nevirapine or abacavir

BACKGROUND: Treatment simplification in antiretroviral-experienced patients receiving protease inhibitor (PI)-containing antiretroviral regimens seems safe, but randomized trials have limited power to detect differences in virological rebound (VR) between different switch strategies. METHODS: From the French Hospital Database on HIV, we selected 2462 patients with undetectable viral load (VL) who switched from a first PI-containing antiretroviral combination (cART) to a combination containing efavirenz (EFV), nevirapine (NVP) or abacavir (ABC). Factors associated with VR and with immunological efficacy (gain of > or = 50 CD4(+) cells/microl) were identified by using Cox models. RESULTS: The 12-month Kaplan-Meier probabilities of VR were 6.8, 13.7 and 12.3% in patients switching to EFV-cART, NVP-cART and ABC-cART, respectively. Factors associated with VR were female sex, younger age, antiretroviral exposure before the first cART, time on first cART, higher VL at first cART initiation, a stavudine/didanosine backbone (rather than zidovudine/lamivudine) after the switch, and a switch to NVP or ABC [respective adjusted hazard ratio versus EFV: 1.53; 95% confidence interval (CI), 1.21-1.94; and 1.53; 95% CI, 1.12-2.08]. When the analyses were restricted to patients who were antiretroviral-naive before their first cART, NVP (but not ABC) was associated with VR. Immunological outcomes did not differ among the three switch regimens. CONCLUSION: When VL is undetectable on a first PI-cART regimen, switching to an EFV-containing regimen is more likely to avoid VR than switching to an ABC or NVP-containing regimen. ABC may be an alternative to EFV for patients who were not exposed to antiretroviral before their first cART regimen, after checking for ABC resistance mutations.     

Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy. INCAS Study Group

BACKGROUND: Current antiretroviral treatment can induce significant and sustained virological and immunological responses in HIV-1-infected persons over at least the short- to mid-term. OBJECTIVES: In this study, long-term immune reconstitution was investigated during highly active antiretroviral therapy. METHODS: Patients enrolled in the INCAS study in The Netherlands were treated for 102 weeks (range 52-144 weeks) with nevirapine (NVP) + zidovudine (ZDV) (n = 9), didanosine (ddl) + ZDV (n = 10), or NVP + ddl + ZDV (n = 10). Memory and na?ve CD4+ and CD8+ T cells were measured using CD45RA and CD27 monoclonal antibodies (mAb), T-cell function was assayed by CD3 + CD28 mAb stimulation, and plasma HIV-1 RNA load was measured by ultra-direct assay (cut-off < 20 copies/ml). RESULTS: Compared to both double combination regimens the triple combination regimen resulted in the most sustained increase in CD4+ T cells (change in CD4+, + 253 x 10(6) cells/l; standard error, 79 x 10(6) cells/l) and reduction of plasma HIV-1 RNA. In nine patients (31%) (ddl + ZDV, n = 2; NVP + ddl + ZDV, n = 7) plasma HIV-1 RNA levels remained below cut-off for at least 2 years. On average, these long-term virological responders demonstrated a significantly higher increase of na?ve and memory CD4+ T cells (P = 0.01 and 0.02, respectively) as compared with patients with a virological failure, and showed improved T-cell function and normalization of the na?ve; memory CD8+ T-cell ratio. However, individual virological success or failure did not predict the degree of immunological response. T-cell patterns were independent of baseline CD4+ T-cell count, T-cell function, HIV-1 RNA load or age. Low numbers of na?ve CD4+ T cells at baseline resulted in modest long-term na?ve T-cell recovery. CONCLUSIONS: Patients with prolonged undetectable plasma HIV-1 RNA levels during antiretroviral therapy do not invariably show immune restoration. Na?ve T-cell recovery in the setting of complete viral suppression is a gradual process, similar to that reported for immune recovery in adults after chemotherapy and bone marrow transplantation.     

Zidovudine/lamivudine/abacavir plus tenofovir in HIV-infected naive patients: a 96-week prospective one-arm pilot study

We evaluated a single-class quadruple nucleoside/nucleotide regimen in a 96-week prospective one-arm pilot study in adult HIV-infected naive patients with CD4 >100 cells/microl. Standard zidovudine/lamivudine/abacavir and tenofovir doses were given. Virologic efficacy was evaluated by intent-to-treat (ITT), switch = failure and on-treatment (OT) analyses. A total of 54 patients were included (median CD4 count 254 cells/microl, VL 79,706 copies/ml). A median drop in VL of 2 log at 14 days and >3 log since week 12 was observed. A total of 34/54 (63%) patients (ITT) and 34/39 (87%) patients (OT) had VL <50 copies/ml at 96 weeks. Four (7%) patients switched therapy due to adverse events, 5 (9%) had virologic failure, and 1 died. Similar efficacy results were observed irrespective of baseline VL (> or <5 log) or CD4 cells (> or <250/microl). A median CD4 gain of +223 cells/microl was achieved. K65R + 41L + 219Q were detected in one patient at virologic failure. Only two patients presented fat loss on clinical evaluation. A decrease in total cholesterol (p = 0.007) and LDLc (p = 0.016) was observed. Our data suggest that zidovudine/lamivudine/abacavir plus tenofovir is a simple, effective, and well-tolerated NNRTI/PI-sparing regimen, even for patients with high viral loads. Larger trials comparing this option with standard initial antiretroviral regimens should be conducted.     

Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study

OBJECTIVE: To determine if long-term improvement in HIV lipoatrophy can be attained by substitution of thymidine analogues zidovudine (ZDV) or stavudine (d4T) with abacavir (ABC). DESIGN: Long-term follow-up (104 weeks) of a randomized, open-label study. SETTING: Seventeen ambulatory HIV clinics in Australia and London. SUBJECTS: Patients with HIV lipodystrophy were randomized to switch from a thymidine analogue to ABC, while continuing all other antiretroviral therapy (ABC arm) (n = 42) or continue current therapy (ZDV/d4T arm) (n = 43). INTERVENTION: At week 24, all control patients could switch to ABC. Of the original 111 patients randomized, 85 had long-term follow-up data, with 77 having imaging data available at 104 weeks. MAIN OUTCOME MEASURE: The primary endpoint was time-weighted change in limb fat mass, measured by dual-energy X-ray absorptiometry (DEXA). RESULTS: At week 104, the mean increase in limb fat for the ABC and ZDV/d4T group was 1.26 +/- 2.02 kg and 0.49 +/- 1.38 kg, respectively. The time-weighted change for limb fat was significantly different between the two arms (0.43 kg; P = 0.008). On-treatment analysis demonstrated a trend for increased limb fat in patients in the ABC arm. Visceral fat accumulation, buffalo hump, self-assessed lipodystrophy or the lipodystrophy case definition score (LCDS) did not improve. CONCLUSIONS: In patients with moderate-to-severe lipodystrophy, significant improvements in subcutaneous fat continued over 104 weeks after switching from a thymidine analogue to ABC. Nevertheless, the lipodystrophy syndrome was still evident, indicating additional strategies need evaluating.     

Relationship of plasma HIV-1 RNA dynamics to baseline factors and virological responses to highly active antiretroviral therapy in adolescents (aged 12-22 years) infected through high-risk behavior

We characterized the viral dynamics of human immunodeficiency virus (HIV) type 1-infected adolescents receiving highly active antiretroviral therapy regimens (lamivudine [3TC]/zidovudine [ZDV]/efavirenz [EFV], 3TC/ZDV/nelfinavir [NFV], or other regimens) and studied the relationship of viral dynamics with baseline factors and virological responses. Viral decay rates for 115 evaluable subjects were estimated from a viral dynamic model. Viral dynamics in HIV-1-infected individuals aged 12-22 years were similar to those of HIV-1-infected adults and infants. Individuals who received 3TC/ZDV/EFV had a more rapid phase 1 viral decay rate than those who received 3TC/ZDV/NFV or other regimens. Phase 1 viral decay rates were positively correlated with baseline RNA levels and week 1 virus load reductions. Our findings indicate that the 3TC/ZDV/EFV regimen may be more potent than 3TC/ZDV/NFV or other regimens and that early viral dynamics or week 1 virus load reduction measurements may be useful in evaluating the potency of antiretroviral regimens.     

Low frequency of renal function impairment during one-year of therapy with tenofovir-containing regimens in the real-world: a case-control study

Concern exists about the risk of nephrotoxicity using tenofovir (TDF) in HIV-infected patients. We performed a retrospective case-control study including 122 consecutive TDF-naive patients who started treatment with TDF-containing regimens and 194 patients receiving antiretroviral therapy with other antiretroviral drugs. During a 12-month observation period 5 (4.1%) patients in the TDF group versus 1 (0.5%) in the control group developed grade 1 or higher serum creatinine elevations (p = 0.018). Only 2 (1.6%) patients discontinued TDF treatment as a result of serum creatinine level elevations. In 4 of the 5 patients developing creatinine elevations TDF was combined with lopinavir-ritonavir. The use of TDF in clinical practice during a 12-month period is associated with low risk of mild renal failure. Further studies to assess long-term renal safety of this drug are needed.     

Response to two consecutive protease inhibitor combination therapy regimens in a cohort of HIV-1-infected children

The response to 2 consecutive protease inhibitor (P1) combination regimens was evaluated in a cohort of HIV-1-infected children. Twelve children, most of whom had been heavily treated, received a 3-drug treatment: saquinavir in hard gelatin capsules (SQVhgc) + zidovudine (ZDV) + didanosine. When this treatment failed it was replaced by a 4-drug regimen: ritonavir + SQVhgc + ZDV + lamivudine. A mild and temporary decrease in viral load (VL) was observed with the initial regimen (p = 0.22). Therapy failure occurred in 7 patients (58%) within 9 months and in another 3 (25%) within 9-18 months. The 7 children who failed within 9 months received the subsequent boosted regimen, leading to a significant and lasting reduction in VL (p = 0.001). None of the patients failed on the boosted regimen: 5/7 achieved a VL of < 400 copies/ml and 3/7 achieved a VL of < 50 copies/ml. Our results suggest that a 4-drug regimen including 2 PIs produces a better and more sustained response than a 3-drug regimen including only 1 PI, and that a good, sustained response is possible with subsequent boosted regimens even in heavily treated children.     

Experience with the use of a first-line regimen of stavudine, lamivudine and nevirapine in patients in the TREAT Asia HIV Observational Database

BACKGROUND: The antiretroviral treatment (ART) combination of stavudine, lamivudine and nevirapine (d4T/3TC/NVP) is the most frequently used initial regimen in many Asian countries. There are few data on the outcome of this treatment in clinic cohorts in this region. METHODS: We selected patients from the TREAT Asia HIV Observational Database (TAHOD) who started their first ART regimen with d4T/3TC/NVP. Treatment change was defined as cessation of therapy or the addition or change of one or more drugs. Clinical failure was defined as diagnosis with an AIDS-defining illness, or death while on d4T/3TC/NVP treatment. RESULTS: The rate of treatment change among TAHOD patients starting d4T/3TC/NVP as their first antiretroviral treatment was 22.3 per 100 person-years, with lower baseline haemoglobin (i.e. anaemia) associated with slower rate of treatment change. The rate of clinical failure while on d4T/3TC/NVP treatment was 7.3 per 100 person-years, with baseline CD4 cell count significantly associated with clinical failure. After d4T/3TC/NVP was stopped, nearly 40% of patients did not restart any treatment and, of those who changed to other treatment, the majority changed to zidovudine (ZDV)/3TC/NVP and less than 3% of patients changed to a protease inhibitor (PI)-containing regimen. The rates of disease progression on the second-line regimen were similar to those on the first-line regimen. CONCLUSION: These real-life data provide an insight into clinical practice in Asia and the Pacific region. d4T/3TC/NVP is maintained longer than other first-line regimens and change is mainly as a result of adverse effects rather than clinical failure. There is a need to develop affordable second-line antiretroviral treatment options for patients with HIV infection in developing countries.     

Adherence to combined Lamivudine + Zidovudine versus individual components: a community-based retrospective medicaid claims analysis

Adherence to a fixed dose combination of dual nucleoside antiretroviral therapy was compared between human immunodeficiency virus (HIV)-infected patients newly started on a fixed dosed combination of lamivudine (3TC) 150 mg/zidovudine (ZDV) 300 mg versus its components taken as separate pills. Medicaid pharmacy claims data were used for analyses. To examine the association between treatment group and medication adherence, three types of multivariate regressions were employed. In addition, all regressions were conducted for the whole population using data from 1995 to 2001 as well as a subpopulation, which excluded data prior to September 1997. Model covariates included patient characteristics, healthcare utilization, and non-study antiretroviral therapy use. The likelihood of > or =95% adherence among patients on combination therapy was three times greater than patients taking 3TC and ZDV in separate pills. Also, combination therapy patients had on average 1.4 fewer adherence failures per year of follow-up and nearly double the time to adherence failure compared to the separate pills group. Consistency among study results suggests that fixed dose combination therapies such as lamivudine (3TC) 150 mg/ zidovudine (ZDV) 300 mg should be considered when prescribing HIV treatment that includes an appropriate dual nucleoside.     

Patient-reported symptoms on the antiretroviral regimen efavirenz/emtricitabine/tenofovir

Most patients (80-90%) newly diagnosed with HIV are started on the antiretroviral regimen efavirenz, emtricitabine, and tenofovir (EFV/FTC/TDF). Existing studies of patient tolerability, however, are limited. We compared symptom experiences of patients on EFV/FTC/TDF, and the subsequent impact on health-related quality of life, with those of patients on other combination antiretroviral therapy (cART). We conducted a cross-sectional analysis of the Veterans Aging Cohort Study from February 2008 to August 2009 to compare the symptom experiences of patients on EFV/FTC/TDF vs. other cART, unadjusted and then adjusted for treatment characteristics, and comorbid disease severity. We then assessed the association between EFV/FTC/TDF use and health-related quality of life. Among the 1,759 patients in our analytic sample, EFV/FTC/TDF use was associated with fewer symptoms than was other cART. The use of EFV/FTC/TDF was independently associated with health-related quality of life, and this association was at least partially explained by symptom burden.     

Quality of life outcomes of combination zalcitabine-zidovudine, saquinavir-zidovudine, and saquinavir-zalcitabine-zidovudine therapy for HIV-infected adults with CD4 cell counts between 50 and 350 per cubic millimeter. PISCES (SV14604) Study Group.

BACKGROUND: This double-blind study evaluated treatment with zalcitabine-zidovudine, saquinavir-zidovudine, or saquinavir-zalcitabine-zidovudine on the health-related quality of life of HIV-infected adults with CD4 cell counts between 50 and 350 cells/mm3. METHODS: Nine hundred and ninety-three HIV-infected male or female quality of life substudy patients aged 18 years or older, with CD4 cell counts between 50 and 350 cells/mm3 na?ve to antiretroviral therapy or with less than 16 weeks of zidovudine therapy, were randomly assigned to one of three daily regimens: zalcitabine 0.75 mg and zidovudine 200 mg every 8 h (ddC/ZDV); saquinavir 600 mg and zidovudine 200 mg every 8 h (SQV/ZDV); or saquinavir 600 mg, zalcitabine 0.75 mg and zidovudine 200 mg every 8 h (SQV/ddC/ZDV). The health-related quality of life was measured using the Medical Outcome Study HIV (MOS-HIV) Health Survey subscale and physical and mental health summary scores, and a global visual analogue scale (VAS) score. The primary health-related quality of life endpoints were the MOS-HIV physical and mental health summary scores. RESULTS: After 24 weeks of treatment, no statistically significant differences were observed between the three treatment groups on physical health and mental health summary scores (global test P = 0.118). After 48 weeks of treatment, statistically significant differences among the groups were observed for physical health and mental health summary scores (global test P = 0.020); no change in physical health summary scores from the baseline were seen in the triple combination therapy, whereas the ddC/ZDV combination therapy group showed decreases from baseline in physical health summary scores (P = 0.008). Six of the 10 individual MOS-HIV subscale scores and the VAS scores showed results consistent with the physical health summary endpoints after 48 weeks of therapy. No statistically significant differences in baseline to 48 week changes in MOS-HIV subscale or summary scores were seen between the ddC/ZDV and SQV/ZDV groups (P > 0.05). CONCLUSIONS: Patients on triple combination therapy maintained their quality of life over 48 weeks compared with significant decreases in the quality of life for ddC/ZDV combination therapy.