Risks and benefits of replacing protease inhibitors by nevirapine in HIV-infected subjects under long-term successful triple combination therapy

Barreiro, Pablo; Soriano, Vincent; Blanco, Francisco J.; Casimiro, Cabrera Abreu; Cruz, Juan; González-Lahoz, Juan

doi:10.1097/00002030-200005050-00006

Cited by 152 publications

(104 citation statements)

References 21 publications

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“…Interestingly, nevirapine, as opposed to the more expensive protease (PR) inhibitors (PIs), is included with two NRTIs in almost all first-line treatment regimens in developing countries (31). Some studies have suggested that nevirapine-based regimens have an antiviral potency similar to that of PI-based regimens while lacking the possible drawbacks inherent in PI-containing regimens, such as lipodystrophy and metabolic alterations (11,41,50,52). In addition, the quick absorption of nevirapine after oral dosing, the ability to cross the placenta, detection in breast milk, a long half-life, and activity against cell-free virions make nevirapine an ideal drug for preventing mother-to-child transmission (23,25).…”

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confidence: 99%

Characterization of a Subtype D Human Immunodeficiency Virus Type 1 Isolate That Was Obtained from an Untreated Individual and That Is Highly Resistant to Nonnucleoside Reverse Transcriptase Inhibitors

Gao

Paxinos

Galovich

et al. 2004

J Virol

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Human immunodeficiency virus type 1 (HIV-1) isolates derived from HIV-infected, treatment-naive Ugandan infants were propagated and tested for sensitivity to antiretroviral (ARV) drugs. Although most subtype A and D isolates displayed inhibition profiles similar to those of subtype B strains, a subtype D isolate identified as D14-UG displayed high-level resistance to nevirapine in peripheral blood mononuclear cell cultures (>2,000-fold) and in MT4 cell cultures (ϳ800-fold) but weaker resistance to delavirdine (ϳ13-fold) and efavirenz (ϳ8-fold) in MT4 cell cultures. To investigate the possible mechanism for this resistance to nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs), the RT coding region in pol was sequenced and compared to the consensus RT sequence of NNRTI-resistant and NNRTI-sensitive subtype A, B, and D HIV-1 isolates. D14-UG did not contain the classic amino acid substitutions conferring NNRTI resistance (e.g., Y181C, K103N, and G190A) but did have some putative sites associated with drug resistance, I135L, T139V, and V245T. Wild-type and mutated protease-RT genes from D14-UG and an NNRTI-sensitive subtype D isolate from Uganda (D13-UG) were cloned into pNL4-3 to produce recombinant viruses and to determine the effects of the mutations on susceptibility to ARV drugs, specifically, NNRTIs. The results showed that I135L and/or V245T mutations can confer high-level resistance to nevirapine and delavirdine as well as low level crossresistance to efavirenz. Finally, ex vivo fitness analyses suggested that NNRTI-resistant sites 135L and 245T in wild-type isolate D14-UG may reduce RT fitness but do not have an impact on the fitness of the primary HIV-1 isolate.Current drugs effective at inhibiting human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) are classified as nucleoside RT inhibitors (NRTIs) and nonnucleoside RT inhibitors (NNRTIs) (3,19). NRTIs interfere with enzyme activity following conversion to the triphosphate forms and incorporation into the growing DNA strand, which causes premature chain termination (4,8). In contrast, NNRTIs are noncompetitive inhibitors which bind a hydrophobic pocket adjacent to the polymerase active site, causing an allosteric change which effectively inhibits DNA polymerization (9). One of the impediments to the frequent use of NNRTIs in combination with at least two NRTIs is the rapid emergence of resistance.Studies of drug resistance have mainly focused on HIV-1 subtype B, which is dominant in developed countries (26). A paucity of data on the emergence of antiretroviral (ARV) drug resistance in individuals or populations infected with other subtypes (e.g., A, C, D, and CRF01) likely is attributable to limited access to ARV drug treatment in developing countries (1, 2, 13, 15, 30-32, 39, 47, 53). However, the rapid implementation of new ARV drug treatment programs in these regions likely will precede thorough investigations of ARV drug resistance in non-clade B HIV-1 isolates. Interestingly, nevirapine, as opposed to the more expensive p...

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confidence: 99%

Characterization of a Subtype D Human Immunodeficiency Virus Type 1 Isolate That Was Obtained from an Untreated Individual and That Is Highly Resistant to Nonnucleoside Reverse Transcriptase Inhibitors

Gao

Paxinos

Galovich

et al. 2004

J Virol

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“…In several randomized to continue with the same PI to simplify the treatment or therapeutic efficacy at 24-48 weeks was similar in both arms and showed improved lipid profile [18][19][20] . In one study there was a greater virological efficacy in the simplification group 20 .In a casecontrol study of a cohort of patients receiving ART in the first IP and replaced by NVP (n = 125) or other IP (new formulation of SQV or PI / r, n = 321) was found at 48 weeks that the relative risk of failure due to change of treatment was 5 times higher with IP than with NVP and there were no differences in the risk of virologic failure 21 . With a different design, in another Spanish study (MULTINEKA) were randomized to 67 patients on stable and CVP <50 copies / mL for at least 6 months to receive LPV / r with NVP or two AN.…”

Section: Nvp Simplificationmentioning

confidence: 97%

Simplification of Antiretroviral Therapy (ART)

Martinez¹

2011

Recent Translational Research in HIV/AIDS

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Recent Translational Research in HIV/AIDS 238 reintroducing the previously recalled. The data at 96 weeks confirmed the durability and safety of this estrategia 3 . After this study, is performed OK04 study including 205 patients with undetectable VL for at least 6 months (median 28), who were taking HAART including LPV/r associated with two NA. Is a randomized, open, non-inferiority comparing the strategy of continuation of triple therapy compared to monotherapy with LPV/r, followed by reinduction with 2 NA if viral rebound appeared. At 48 weeks the percentage of patients without virologic failure was 90 and 94% respectively (difference, -4%, upper limit 95% CI for difference 3.4%, meeting the criteria for noninferiority). The percentage of patients with VL <;50 copies/mL at 48 weeks (ITT), considering as failures reinduction was 85% in the monotherapy group and 90% in the continuation (p = 0.31). Episodes of low-level viremia between 50 and 500 copies / mL were more frequent in patients treated with monotherapy (4 vs. none) 4 . With patients in these two studies performed a multivariate analysis of predictors of loss of virologic response in the group treated with LPV/r monotherapy. Virologic failure was associated with lack of grip, low haemoglobin levels and nadir CD4 <100 cells/μL 5 . In another study of simplification to monotherapy with LPV/r was somewhat different strategy. We included 155 previously untreated patients who were randomized 2:1 to treatment with ZDV/3TC start with LPV / r (n = 104) or EFV (n = 51). Within 24 weeks of treatment and after at least 3 controls with VL < 50 copies / mL, patients taking LPV maintenance came to LPV/r monotherapy. Whereas failure to any positive viremia at 96 weeks of follow up, 48% of patients treated with LPV / r and 61% with EFV had CVP < 50 copies / mL (p = 0.17, 95% of the difference, -29% to 4%). In a new analysis that included patients as responders to reintroduce them after getting back NA CVP < 50 copies / mL, 60% of patients on LPV/r and EFV 63% responded to treatment ( p = 0.73, CI 95% -19% 13%). Have been observed low viral loads in patients on monotherapy. As for security, lipoatrophy was observed in 5% of the monotherapy arm, compared to 34% of the EFV group. There were no differences in lipohypertrophy. Grade 3-4 lipid abnormalities were more frequent in the group of LPV/r. In these two studies highlights the importance of the period during which the CVP remains undetectable prior to the step alone. This same strategy is being explored and DRV/r 6,7 ATV/r 8,10 . They have published the results at 48 weeks of a pilot study, single-arm open-simplification to ATV / r, the ACTG 5201. Were included in the same 34 patients who started treatment with 2 NA and IP, who were with undetectable viral load (<50 copies / mL) for at least 48 weeks, had not been treated with NN or prior virologic failure were HBsAg negative. Upon entering the study were switched to IP they were taking on ATV / r and 6 weeks after suspending the AN. The primary endpoint was time to ...

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“…These studies were all conducted in economically developed countries, mainly in Europe (the UK, Spain, Italy and France), with one each in the USA and Australia. Seven publications reporting results from randomized switch protocols were reviewed in great detail and are discussed comprehensively [10][11][12][13][14][15][16][17]. Two major retrospective cohort studies are considered [18][19][20].…”

Section: Selected Literaturementioning

confidence: 99%

“…In fact, some studies suggest that the risk of virological breakthrough is diminished as a result of improved adherence [17]. In general, published switch studies have involved subjects without prior NNRTI exposure.…”

Section: Variables Determining Switch Efficacymentioning

confidence: 99%

“…In fact, several short-term switch studies have reported improved metabolic profiles [16,17,[25][26][27] (Table 3). There is considerable variation in the results of these short-duration evaluations because of heterogeneous study populations, differing definitions and methods of evaluating metabolic changes, and nonstandardized backbone antiretrovirals.…”

Section: Variables Determining Switch Efficacymentioning

confidence: 99%

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Evaluation of nevirapine‐switch strategies for HIV treatment

Cooper

2006

HIV Medicine

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Despite the benefits of protease inhibitor (PI)-based HIV treatment, issues of tolerability, dosing frequency, pill count and long-term metabolic complications necessitate evaluation of alternate treatment strategies. The weight of evidence demonstrates that a switch from a PI-based regimen to one containing nevirapine can be accomplished safely while maintaining virological suppression. There is no immunological cost. There is probably an overall benefit in terms of the metabolic milieu.

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Risks and benefits of replacing protease inhibitors by nevirapine in HIV-infected subjects under long-term successful triple combination therapy

Abstract: The replacement of PI by NVP seems to be safe both virologically and immunologically, provides a significant improvement in the quality of life and in half of patients ameliorate lipodystrophic body-shape changes at 6 months, although serum lipid abnormalities still remain unmodified.

Cited by 152 publications

References 21 publications

Characterization of a Subtype D Human Immunodeficiency Virus Type 1 Isolate That Was Obtained from an Untreated Individual and That Is Highly Resistant to Nonnucleoside Reverse Transcriptase Inhibitors

Characterization of a Subtype D Human Immunodeficiency Virus Type 1 Isolate That Was Obtained from an Untreated Individual and That Is Highly Resistant to Nonnucleoside Reverse Transcriptase Inhibitors

Simplification of Antiretroviral Therapy (ART)

Evaluation of nevirapine‐switch strategies for HIV treatment

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