Long-term efficacy and safety of nevirapine-containing regimens in virologically suppressed patients: a 17-year follow up

Abstract

Background: To evaluate long term outcomes in patients maintaining a NVP based regimen for more than 10 years.

Materials and methods: Retrospective, multicenter, cohort study including virologically suppressed patients, currently receiving a NVP-based regimen that had been started at least 10 years previously. Demographic, clinical, and analytical variables were recorded.

Results: Two hundred and seventy four subjects were included. Median (IQR) follow up was 17.1 (13.8–18.5) years. Dyslipidemia (29.9%), hypertension (11.4%) and diabetes (8%) were the most common reported co-morbidities. After a median of 17 years of follow-up we observed a significant increase in general health markers such as hemoglobin and CD4 cells (all p<0.001) as well as a significant reduction in CD8 and ALT [−111 cells/uL (−346.5−151) p 0.003 and ALT median (IQR) -4.2 (−18.5−4) p<0.001 respectively]. LDL-c and serum triglyceride levels decreased significantly [−0,1 (−1−0.6) p:<0.001 and −0,3 (−1.2−0.4) p:0.002 respectively]. HDL-c increased significantly 0.3 (00.5−0.6). Median (IQR) time with persistent HIV VL <50 copies was 16 (13−18) years. During follow up, subjects presented with median (IQR) 1 (0-2) blip (HIV VL >50<1000 copies/ml).

Conclusions: Based on the extensive experience as well as a good tolerance and efficacy profile, NVP should be considered for treatment continuation in those patients already receiving this inexpensive generic drug.

Keywords:

• Nevirapine
• antiretroviral therapy
• long term
• outcomes

Background

Combined antiretroviral therapy (cART) is the standard of care for HIV-infected patients.¹

This has led to improved outcomes for patients including extended life.²

There are several families of antiretroviral drugs that are now available for the treatment of HIV-1 infection, providing multiple treatment options for individuals who are newly diagnosed or chronically infected.³ cART regimens that include the integrase strand transfer inhibitor (INSTI) class have demonstrated high efficacy, tolerability and they are now considered as a first option in those patients initiating treatment.⁴ However a vast majority of patients are stable and have been receiving other class families of antiretroviral for years.

The non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (NVP) is one of the “oldest” currently available antiretroviral (ARV) drugs, first commercialized in 1997. NVP has been effectively used for many years and despite the development of many new ARV compounds since then, there are still a substantial number of patients receiving this drug worldwide, especially in developing countries.⁵ Moreover, Nevirapine may be a cost effective option compared to more recent agents. However there is a gap in the literature on long term NVP follow up 10 years and over.

The objective of this study is to describe the efficacy and safety outcomes in patients who remained receiving a NVP-based therapy for 10 years and over in a large multi-centre cohort.

Methods

This is a retrospective, observational, multicenter cohort study, including adult HIV-infected patients from 4 Hospitals in Barcelona, Spain with extensive experience in HIV management.

Using local database we indentified all subjects who had been receiving a NVP-containing regimen for more than 10 years and at the time they were included in this analysis. Only those subjects who initiated and remained receiving NVP were eligible for this analysis. Those who interrupted NVP before data collection with disregard of the reason were excluded.

The primary end points were liver, lipid, and CD4 outcomes. Baseline demographic information was documented, and the following data were recorded for yearly analysis: CD4 count, viral load, full blood count, alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), gamma-glutamyl transpherase (GGT), glucose, creatinine, cholesterol, triglycerides and HDL-cholesterol (HDL-c), and LDL-cholesterol (LDL-c) levels. Co-morbidities (dyslipidemia, hypertension, diabetes, Hepatitis B and/or C co-infection, chronic liver disease, non-alcoholic fatty liver disease, cardiovascular disease and renal disease) reported at baseline and during follow-up will be introduced to the analysis.

Statistical analysis

Results for continuous variables are presented as the median of the absolute values or as the median change from baseline and the interquartile range (IQR). Results for categorical variables are presented as frequencies and percentages. Between-group comparisons of continuous variables were performed with the independent t-test for those with a normal distribution and the Mann Whitney U test for those with a non-normal distribution. Comparisons between follow-up and baseline results of continuous variables were carried out with the t-test for repeated measures in those with a normal distribution and Wilcoxon’s signed-rank test in those with a non-normal distribution. A two-sided significance level of 0.05 was used in all comparisons. Analyses were performed with PASW Statistics, version 18.0.0 (SPSS, Inc., 2009, Chicago, IL, www.spss.com).

Results

Two hundred and seventy four subjects were included. Median (IQR) follow up was 17.1 (13.8–18.5) years. Most patients were male (77%). Mean age at baseline was 40 years, mean (SD) HIV viral load (VL) and CD4 count were 40,827 (175,570) copies/ml and CD4 492 (328)/uL respectively. One third of the patients initiated a first ARV treatment including NVP (33%), 25% suppressed patients switched to NVP while in 42% pretreated subjects initiated a NVP-containing regimen with detectable HIV VL. At baseline, NVP was frequently combined with lamivudine (3TC)/zidovudine (36.6%) or 3TC/stavudine (25.2%). Dyslipidemia (29.9%), hypertension (11.4%) and diabetes (8%) were the most common reported co-morbidities at baseline and during follow-up. Coronary artery disease (2.9%), chronic kidney disease (2.2%) and significant liver damage (2.5%) were less prevalent in this group. Twenty one percent of the subjects were HCV + and 4.7% presented with chronic hepatitis B. At baseline, median (IQR) hemoglobin was 141 (133–149.8) g/L; platelets 215 (180.5–258.7) ×10⁹/L; ALT 27.8 (18.9–42.7) IU/L; AST 25 (19.8–31) IU/L; GGT 35.7 (22.8–60.9) U/L; total-cholesterol 4.94 (4.2–6) mmol/L; HDL-c 1.1 (0.9–1.4) mmol/L; LDL-c 3 (2.56–4.16) mmol/L; triglycerides 1.5 (1–3) mmol/L and serum creatinine 95 (80.5–108.8) mmol/L. After a median of 17 years of follow-up we observed a significant increase in general health markers such as hemoglobin [median (IQR) increase 9 g/L (−0.55–19.7) p < 0.001] and CD4 cells [median (IQR) increase 307/uL (112.7–598.5) p < 0.001], as well as a significant reduction in CD8 cells [median (IQR) −111 cells/uL (−346.5–151) p 0.003] and ALT [median (IQR) −4.2 (−18.5–4) p < 0.001]. Median (IQR) LDL-c and serum triglyceride levels decreased significantly −0.1 (−1.–0.6) p < 0.001 and −0.3 (−1.2–.0.4) p:0.002 respectively. HDL-c increased significantly 0.3 mmol/L (0.05–0.6) p < 0.001.

Median (IQR) time with persistent HIV suppression (<50 copies/ml) was 16 (13-18) years.

Median (IQR) platelets increase was 2 × 10⁹/L [(−31.7–39.5) p 0.5] and serum creatinine decreased −1.14 mmol/L [(−11.6–12) p 0.6]. Unfortunately glucose and ALP results were incomplete. Further variables are presented in Table 1.

Table 1 Changes from baseline to follow up

Variable	Baseline Median (IQR)	Current Median (IQR)	Median (IQR) change from baseline	p-value
Hemoglobin g/L	141 (133–149,8)	150 (141,5–160)	9 (−0,55–19,7)	<0,001
Platelets × 10^9/L	215 (180,5–258,75)	213,5 (176–262,75)	2 (−31,75–39,5)	0,588
CD4 cells/uL	437,5 (250–643,75)	768 (569,5–1034,25)	307 (112,75–598,5)	<0,001
CD8 cells/uL	896 (644,5–1246,5)	766 (612,5–1127,5)	−111 (−346,5–151)	0,003
ALT IU/L	27,8 (18,9–42,7)	22 (17–31,4)	−4,2 (−18,15–4)	<0,001
AST IU/L	25 (19,8–31)	23 (18–28)	−1,2 (−10–4)	0,032
GGT U/L	35,7 (22,8–60,9)	51,9 (34–81,25)	12 (−4,85–37,35)	<0,001
COL mmol/L	4,94 (4,29–6,03)	5,08 (4,46–5,58)	0,03 (−0,9–0,9)	0,891
HDL-c mmol/L	1,19 (0,95–1,42)	1,53 (1,16–1,86)	0,37 (0,05–0,65)	<0,001
LDL-c mmol/L	3,03 (2,56–4,16)	2,93 (2,53–3,59)	−0,11 (−1,01–0,67)	0,191
TG mmol/L	1,58 (1,03–3,09)	1,5 (1,01–2,12)	−0,31 (−1,26–0,44)	0,002
Creatinine mmol/L	95,02 (80,5–108,8)	92,76 (79–111,43)	−1,14 (−11,66–12)	0,648

(During follow up, subjects presented with median (IQR) 1 (0-2) blips (HIV VL < 1000 copies/ml). Most frequent current combinations are NVP + ABC/3TC in 48.5%, +FTC/TAF 17.5% and + TDF/FTC in 9.1%. No statistical significant differences were observed in safety parameters between those who initiated with NVP, those who switch whilst suppressed and those who witched while HIV VL was detectable.

Discussion

In this long-term study with a median follow-up of 17 years, NVP-containing regimens were associated with an improvement from baseline in clinical variables related to general health status, such as hemoglobin as well as increased CD4 count, preserved liver markers as well as lipid profile. To our knowledge, this study contains the longest clinical follow-up data related to the use of NVP-containing regimens.

Since most serious adverse events associated with NVP are seen during the first few weeks/months of the therapy, long term NVP exposure seems to be as safe as effective as other first or second line drugs.⁶ In a recently published study NVP was shown to be as good as efavirenz in patients stable on NVP treatment for years, providing evidence against switching off NVP in this population.⁷

Our data are consistent with those from previous cohort studies assessing NVP regimens administered for long periods (up to 6 years).^8,9

Moreover, NVP is recognized as one ARV drugs with the lowest impact on the lipid profile,^10–12 and it has been associated with better lipid profiles than other non-nucleoside reverse transcriptase inhibitors or protease inhibitors. NVP is the ARV compound associated with the highest HDL-c concentrations, with increases reaching up to 40% in previous studies.¹³ Our data further support these results, as is seen in the TG decrease and a significant increase in HDL-c from baseline. LDL-c also decreased.

Treatment switch from NVP to the newer NNRT rilpivirine has been shown to maintain virological suppression as well as to improve lipid profile.¹⁴ However food restrictions as well as the increased cost of this approach maybe limiting in low income countries. This study has some limitations inherent to its retrospective design. It can be also argued that the study does not provide information on the proportion of patients initiating a NVP regimen who had to discontinue the drug. We recognize that our patient population is biased because patients discontinuing nevirapine have been excluded. It is well known that a proportion of about 13-20% of patients initiating a nevirapine-containing regimen used to stop the drug because of toxicities/virologic failure within the first year of follow-up, and this has been described in several papers.^8,15,16 However, our aim was to focus on the benefits obtained in several relevant clinical aspects occurring in patients initially tolerating NVP and maintaining the regimen in the long term. We believe that our study offers valuable information on the use of long-term NVP-containing regimen in routine clinical practice and provides clinicians with data to support decision-making in this population.

Treatment expenses in developing countries are one of the main barriers to expand access to HIV therapy. There are still thousands of subjects receiving NVP based regimens worldwide, especially in resource limited settings.^17–21 Maintaining NVP-based regimens in those patients already under long term NVP exposure and no needs of treatment modification could save significant money to treat more people.

Based on the extensive experience as well as a good tolerance and efficacy profile, NVP should be considered for treatment continuation in those patients already receiving this inexpensive generic drug, especially in resource-limited setting.

Transparency declarations

None to declare.

Additional information

Funding

Study data have been generated as part of the routine work the HIV Unit. No funding of any kind has been received for this work.

Notes on contributors

Juan Tiraboschi

Dr Juan Manuel Tiraboschi He obtained a Medical Degree from the National University of Córdoba, Argentina in 1999. He trained in Medicine and Infectious Diseases in Argentina and France (2000–2007). He obtained a PhD degree in 2015 by the University of Barcelona investigating on “Penetration and antiviral activity of antiretroviral drugs in the Central Nervous System”. Between 2013 and 2016, Dr. Tiraboschi completed a fellowship as Clinical Research Doctor in HIV at St Thomas Hospital in London, UK. He joined the HIV and STI Unid at Bellvitge University Hospital in 2016. His clinical and research interests include the effects of HIV and antiretroviral therapy on Central Nervous System and viral reservoirs.

Natalia Lattour

Dr Natalia Lattour trained in Infectious Diseases at the Hospital San Martin in La Plata, Argentina between 2014 and 2019. In 2018 she completed a two month stage at the HIV and STI Unit of the Bellvitge University Hospital in Barcelona. She is currently working as an ID specialist in Buenos Aires, Argentina.

Hernando Knobel

Dr Hernando Knobel Head of the Infectious Diseases Service, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain.

Pere Domingo

Pere Domingo is currently Senior Consultant and HIV/AIDS Program Director at the Infectious Diseases Unit of the Hospital de la Santa Creu i Sant Pau, in Barcelona. He graduated with honours in the University of Barcelona in 1980 and achieved his PhD degree in the Autonomous University of Barcelona in 1993 (Magna cum laude). He has been devoted to infectious diseases and HIV-1 infection since 1989. He is Associate Professor of Medicine at the Medicine School (Autonomous University of Barcelona) since 1994. He has authored or co-authored more than 500 scientific papers and more than 100 book chapters. He has been the speaker in more than 400 meetings or congresses, and is currently reviewer for more than 50 international journals, international agencies, and international meetings and conferences. He is now member of 7 Editorial Boards of medical journals. Dr. Domingo is expert member of the Spanish Medicines Agency and of the European Medicines Agency. His main research interests are antiretroviral therapy and its complications, especially fat redistribution syndromes, metabolic alterations, insulin resistance, cardiovascular risk, and early senescence, but also meningococcal disease and bacterial meningitis in adults. Dr. Domingo is the past President of the Spanish AIDS study group (2011-2013), of the Spanish Society of Infectious Diseases and Clinical Microbiology. He currently coordinates evaluation of research project in the area of Clinical Medicine and Epidemiology for the Spanish National Evaluation Agency.

Esteve Ribera

Dr Esteve Ribera Senior Consultant in HIV and Infectious Diseases at the Vall d' Hebron Hospital in Barcelona, Spain.

Daniel Podzamczer

Dr Daniel Podzamczer He qualified from the University of Buenos Aires and undertook training in Internal Medicine at Bellvitge University Hospital (Barcelona, Spain). He obtained a PhD degree in 1991 investigating on “predictors of progression to AIDS” (University of Barcelona, Spain). He started to see HIV-infected patients in the first years of the epidemic, that is in the mid of 80’. Thus he has lived very different periods in the history of AIDS. Beginning when AIDS was a fatal disease and patients died every day until now when HIV has become a chronic disease with a prolonged survival and an excellent life quality of patients receiving antiretroviral therapy. He is currently the head of an HIV and STI Unit within an Infectious Disease Service in a University teaching hospital in Barcelona. In his position he has contributed to clinical research, participating and organizing clinical trials related to opportunistic infections, HIV complications and antiretroviral therapy. He is a co-author of more than 250 scientific papers published in national and international Journals such as New Engl. J Med, Lancet, Ann Intern Med, Clin. Infect Dis., J Infect Dis., AIDS and JAIDS among others. He has also participated in expert panels for Guidelines for the management of opportunistic infections (NIH/CDC/IDSA), antiretroviral therapy, opportunistic infections and neurocognitive disorders (GESIDA). He is also a peer reviewer for a number of international Journals.