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PubMed2000

Decreased HIV-associated T cell apoptosis by HIV protease inhibitors.

Antiretroviral treatment of patients infected with HIV results in improvements in CD4+ T cell number. Emerging evidence suggests that some of the improvements in CD4+ T cell number that occur in response to protease inhibitor (PI) therapy may not be accounted for solely by enhanced viral suppression, implying that PI may directly affect T cell survival. Since HIV T cell depletion is associated with enhanced apoptosis, we analyzed the effect of PIs on T cell apoptosis. In vitro treatment of peripheral blood lymphocytes (PBLs) from HIV-infected but untreated patients with reverse transcriptase inhibitors (RTIs) does not alter apoptosis, whereas PI treatment rapidly reduces CD4+ and CD8+ T cell apoptosis. In contrast, PI treatment does not alter apoptosis in PBL blasts from HIV-negative patients, or in Jurkat T cells. Consistent with this observation, 8 days of PI therapy in HIV-infected patients does not significantly alter plasma viremia, yet results in significant inhibition of CD4+ and CD8+ T cell apoptosis. The inhibitory effects of PI on apoptosis have implications concerning the treatment of HIV and its pathogenesis.

Apoptosis↗
PubMed2000

Initial therapy with protease inhibitor-sparing regimens: evaluation of nevirapine and delavirdine.

We have compared the results (on-treatment analyses) of 2 randomized clinical trials of protease inhibitor-sparing regimens in drug-naive patients. In the INCAS (Italy, Netherlands, Canada, Australia) study, the mean decrease in plasma viral load over 52 weeks was 2.2 log(10) copies/mL in 40 patients who were receiving zidovudine/didanosine/nevirapine (18 [45%] had maximal suppression), with a mean increase in CD4 T cell counts of 139 cells/microL. In protocol 0021 Part II, the mean decrease in plasma viral load over 52 weeks was 2.1 log(10) copies/mL in 34 patients who were receiving zidovudine/lamivudine/delavirdine (20 [59%] had maximal suppression), with a mean increase in CD4 T cell counts of 88 cells/microL. The virologic and immunologic efficacy of the 2 triple-drug regimens are similar. Until results of long-term studies are available to establish whether a preferred approach to initial therapy exists, nonnucleoside reverse transcriptase inhibitors may be a valuable alternative to protease inhibitors in the initial therapy of antiretroviral-naive, moderately immunosuppressed patients.

Anti-HIV Agents↗
PubMed2001

Resistance of human immunodeficiency virus type 1 to reverse transcriptase and protease inhibitors: genotypic and phenotypic testing.

Treatment of HIV-1-infected persons with antiretroviral drugs including reverse transcriptase (RT) and protease inhibitors has significantly reduced the rate of HIV and AIDS-related morbidity and mortality. However, these treatments can select for drug-resistant viruses which are associated with poor virologic responses to the antiretroviral therapies and loss of clinical benefit. Drug resistance is conferred by single or several amino acid changes in the pol gene. These mutations can be classified as primary when they directly confer reduced drug susceptibility, or secondary when their influence is primarily on replication capabilities of resistant viruses. Both genotypic and phenotypic methods are used for drug resistance testing. Genotypic assays detect resistance-related mutations by sequence analysis or point mutations assays. Phenotypic testing measures drug susceptibility of patient-derived viruses in culture assays. Viruses can be conventionally isolated from peripheral blood lymphocytes, or generated more rapidly through recombination of plasma-derived RT/protease sequences and modified HIV-1 vectors. Phenotypic testing provides direct evidence of resistance, is easy to interpret, but is laborious and expensive. In contrast, genotypic testing provides indirect evidence of resistance, is relatively faster and cheaper, but some complex mutation patterns may be difficult to interpret. Non-culture based phenotypic assays that measure susceptibility of RT activity in plasma to RT inhibitors have been described recently, and provide new tools for rapid phenotypic testing. Resistance testing is currently recommended to help guide the choice of new regimens after treatment failure and for guiding therapy in pregnant women.

Anti-HIV Agents↗
PubMed2006

Amdoxovir versus placebo with enfuvirtide plus optimized background therapy for HIV-1-infected subjects failing current therapy (AACTG A5118).

BACKGROUND: Amdoxovir (2,6-diaminopurine dioxolane; DAPD) is a nucleoside reverse transcriptase inhibitor (NRTI) of human immunodeficiency virus-1 (HIV-1) with activity against wild-type and NRTI-resistant viruses. METHODS: ACTG A5118 assessed the antiretroviral activity and safety of DAPD (300 mg orally, twice daily) versus placebo in combination with enfuvirtide (ENF) plus an optimized background (OB) regimen in subjects with failure of two or more antiretroviral (ARV) regimens. The primary endpoints for comparison were time-averaged area under the curve minus baseline (AAUCMB) of plasma HIV-1 RNA concentration at 24 weeks and time to first serious (DAIDS toxicity table Grade > or = 3) adverse event (AE). An unplanned interim review recommended closing enrollment because the study was unlikely to demonstrate a difference between arms. The 18 subjects on study, nine in each arm, were unblinded and allowed to continue study treatment through 48 weeks. RESULTS: Intention-to-treat analysis showed the median AAUCMB was -0.9 log10 copies/mL (95% CI = -2.2, -.0.1) in the DAPD arm and -0.9 log10 copies/ml (95% CI = -1.1, -0.1) in the placebo arm (P = 0.69). Median CD4+ T-cell increase was 79 cells/mm3 (95% CI =1, 115) in the DAPD arm and 60 (95% CI =1, 101) in the placebo arm (P = 0.45). Time to first serious AE did not differ between arms (P = 0.91). Mild decreases of creatinine clearance were observed with similar frequency between arms; no subject developed lens opacities. CONCLUSIONS: Addition of DAPD to ENF plus OB in advanced subjects with highly resistant virus appeared safe, but did not add statistically significant antiretroviral activity at 24 weeks in this small study.

Adult↗
PubMed1999

Virological efficacy and plasma drug concentrations of nelfinavir plus saquinavir as salvage therapy in HIV-infected patients refractory to standard triple therapy.

Therapeutic options are limited for patients refractory to triple therapy with two reverse transcriptase inhibitors and one protease inhibitor. Preliminary results showing favorable effects of protease inhibitor combination therapy with nelfinavir and saquinavir due to inhibition of metabolism by cytochrome P450 (CYP450) prompted us to study this combination. - Thirteen patients with incomplete suppression of plasma HIV-RNA were enrolled and treatment was started with nelfinavir 750 mg tid and saquinavir 400 mg bid. Saquinavir-dosage was escalated in weekly intervals to 400 mg tid and 600 mg tid, respectively. All doses were given with food, and plasma levels of saquinavir and nelfinavir were assessed 4 hours post-dosing after 1, 2, 3, 4 and 8 weeks. Treatment was considered virologically efficacious if HIV-viral load was reduced by at least 0.5 log10 from baseline. - Double protease inhibitor-treatment with nelfinavir and saquinavir was virologically efficacious in 5/13 (39%) patients after 4 weeks but only in 4/13 (31%) patients after 8 and 1/13 (8%) after 16 and 24 weeks, respectively. No statistical difference in plasma concentrations was observed when saquinavir was administered in increasing doses of 400 mg bid, 400 mg tid or 600 mg tid in combination with nelfinavir. 5/13 (39%) patients developed diarrhea (>4/d), no other serious side-effects were observed. By eight weeks, the mean CD4 count for all patients was significantly higher when compared to baseline. - In patients refractory to standard triple therapy the combination of nelfinavir and saquinavir showed significant elevation of CD4-count, but only short term virological efficacy in a minority of patients. Plasma concentrations of saquinavir could not be increased by weekly dose escalation of the drug from 400 mg bid to 600 mg tid. Saquinavir drug concentrations of 600 mg saquinavir tid and nelfinavir showed rather non-significant lower values when compared to historical controls treated with a double-dose 1200 mg saquinavir tid regimen alone. We conclude that in these patients the combination of nelfinavir plus saquinavir has no advantage in terms of increasing bioavailibility of saquinavir or virological efficacy. During short observation time a beneficial effect on CD4-count was observed.

Adult↗
PubMed1996

New strategies for treating AIDS.

To date, the effective management of HIV-1 infection by anti-retroviral drugs has proved remarkably difficult to achieve. This is primarily due to the ease with which HIV-1 becomes resistant to drugs which initially may be very effective at blocking viral replication. In a recent issue of Science, two promising new AIDS treatments were reported. The first described the use of retroviral-type zinc finger structures found in the HIV-1 nucleocapsid protein as targets for antiretroviral drugs. THe second demonstrated the feasibility of the reverse transcriptase inhibitor (R)-9-(2-phosphonylmethoxypropyl) adenine as a postexposure prophylaxis in blocking HIV-1 infection.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Investigating the effects of stereochemistry on incorporation and removal of 5-fluorocytidine analogs by mitochondrial DNA polymerase gamma: comparison of D- and L-D4FC-TP.

Enantiomers of beta-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine (D/L-D4FC) are nucleoside analog reverse transcriptase inhibitors (NRTIs) currently under investigation as antiviral agents. One of the major problems of NRTIs is toxicity to mitochondria. It has been shown that mitochondrial toxicity of NRTIs can correlate with incorporation and removal of these compounds by mitochondrial DNA polymerase (Pol gamma). Mechanistic studies have shown that, if activated, NRTIs are incorporated more efficiently by HIV-1 reverse transcriptase (RT) and less efficiently by Pol gamma, the corresponding nucleosides are considered to be more selective. In the present study, in order to predict potential DNA Pol gamma-related mitochondrial toxicity of D- and L-D4FC, the incorporation and removal of the monophosphate form of these compounds by Pol gamma were studied using transient kinetic methods. Our cell-free results showed that Pol gamma incorporated the natural D-isomer significantly more efficiently than the unnatural L-isomer. However, the removal rates of these enantiomers from the chain-terminated primers were almost identical. While these results suggest that D-D4FC may present more mitochondrial toxicity than L-D4FC in cell-free assays, we have previously shown that HIV-1 RT prefers D-D4FC-TP as a substrate over the L-isomer, particularly in the case of mutant forms of RT associated with nucleoside drug resistance such as M184V. Since the effectiveness of NRTIs is a balance between efficiency of incorporation by wild-type and drug-resistant forms of HIV-1 RT and mitochondrial toxicity, our kinetic results suggest that both enantiomers may show promise as potential therapeutics.

Anti-HIV Agents↗
PubMed2002

Dose proportional inhibition of HIV-1 replication by mycophenolic acid and synergistic inhibition in combination with abacavir, didanosine, and tenofovir.

Mycophenolate mofetil (MMF), a therapeutically used inhibitor of inosine monophosphate dehydrogenase is hydrolyzed to its active metabolite mycophenolic acid (MPA) in vivo. MPA exhibits anti-HIV activity in vitro. We tested MPA alone and in combination with abacavir (ABC), didanosine (DDI), lamivudine (3TC) and tenofovir (TFV) against wild-type human immunodeficiency virus type-1 (HIV-1) and nucleoside reverse transcriptase inhibitor (NRTI)-resistant HIV-1. MPA (62.5-500 nM), when combined with ABC or DDI, synergistically enhanced activity against wild-type HIV and the NRTI-resistant HIV clone DRSM34. MPA also enhanced the activity of TFV against both wild-type HXB2 and TFV-resistant strain HIV(K65R), in a more than additive manner. No significant antiproliferative effect of MPA (< or =0.25 microM) alone or in the presence of ABC, DDI and TFV was observed. This indicates that the antiviral effects of MMF may be clinically achievable without fully blocking T-cell proliferation or inducing immunosuppression. These findings provide further rationale for the clinical testing of MMF in combination with ABC, DDI, and TFV.

Adenine↗
PubMed2002

A randomized trial assessing the impact of phenotypic resistance testing on antiretroviral therapy.

OBJECTIVE: To compare the effect of treatment decisions guided by phenotypic resistance testing (PRT) or standard of care (SOC) on short-term virological response. DESIGN: A prospective, randomized, controlled clinical trial conducted in 25 university and private practice centers in the United States. PARTICIPANTS: A total of 272 subjects who failed to achieve or maintain virological suppression (HIV-1-RNA plasma level > 2000 copies/ml) with previous exposure to two or more nucleoside reverse transcriptase inhibitors and one protease inhibitor. INTERVENTIONS: Randomization was to antiretroviral therapy guided by PRT or SOC. MAIN OUTCOME MEASURES: The percentage of subjects with HIV-1-RNA plasma levels less than 400 copies/ml at week 16 (primary); change from baseline in HIV-1-RNA plasma levels and number of "active" (less than fourfold resistance) antiretroviral agents used (secondary). RESULTS: At week 16, using intent-to-treat (ITT) analysis, a greater proportion of subjects had HIV-1-RNA levels less than 400 copies/ml in the PRT than in the SOC arm (P = 0.036, ITT observed; P = 0.079, ITT missing equals failure). An ITT observed analysis showed that subjects in the PRT arm had a significantly greater median reduction in HIV-1-RNA levels from baseline than the SOC arm (P = 0.005 for 400 copies/ml; P = 0.049 for 50 copies/ml assay detection limit). Significantly more subjects in the PRT arm were treated with two or more "active" antiretroviral agents than in the SOC arm (P = 0.003). CONCLUSION: Antiretroviral treatment guided prospectively by PRT led to the increased use of "active" antiretroviral agents and was associated with a significantly better virological response.

Adult↗
PubMed2002

Ritonavir plus saquinavir versus single protease inhibitor therapy in protease inhibitor-naive HIV-infected patients: the Swiss HIV Cohort Study.

OBJECTIVES: To compare the response to ritonavir (RTV) plus saquinavir (SQV) with single protease inhibitor (PI) therapies among PI-naive HIV-1 infected individuals. METHODS: Response to treatment was analysed according to the intent-to-treat principle in a prospective observational cohort study of 177 patients who between May 1995 and March 2000 started a double PI therapy with RTV and SQV (nonboosting dosages) plus at least one nucleoside reverse transcriptase inhibitor (NRTI) and 2,214 patients with a single PI therapy plus two NRTIs. We used survival analysis and Cox's proportional hazard regression methods. The primary endpoint was the time to a plasma viral load of < 400 copies/mL. Secondary endpoints were taken as a gain in the CD4 count of >100 cells/microL, and change of initial PI for any reason. RESULTS: Baseline characteristics in both treatment groups were balanced. Median follow-up in both groups was 10.4 months. Time to an HIV-1 viral load of < 400 copies/mL and an increase in the CD4 count of >100 x 10(6) cells/L was shorter for RTV plus SQV compared with single PI regimens (log rank test for each endpoint P < 0.05). The adjusted hazard ratios of RTV plus SQV compared with single PI regimens were 1.21 (95% confidence interval 0.99-1.47) for achieving an HIV-1 viral load of < 400 copies/mL, 1.12 (0.88-1.42) for an increase in the CD4 count of > 100 cells/microL, and 0.90 (0.73-1.11) for change of first PI regimen. CONCLUSIONS: Treatment with RTV plus SQV compared with single PI regimens appeared to give similar results for virological or immunological response.

Adolescent↗
PubMed1999

Protease inhibitors as initial therapy for individuals with an intermediate risk of HIV disease progression: is more necessarily better?

OBJECTIVE: To compare three possible therapeutic strategies for the treatment of patients with an intermediate risk of HIV disease progression. DESIGN: Mathematical modeling based on assumptions derived from published data. METHODS: A parametric survival model was fitted to empirical data to describe the survival trajectory of untreated individuals. It was assumed that successful treatment decreases the risk of disease progression curing the first year after its introduction by a constant that is dependent on the magnitude of the initial drop in HIV viral load. Thereafter, individual members of the treatment cohort follow different pathways, depending on the duration of the initial response or, in case of virologic failure, the response to a new drug regimen. RESULTS: Sub-groups of patients starting therapy with two nucleoside reverse transcriptase inhibitors (NRTI) or two NRTI and a protease inhibitor had the highest instantaneous risk of disease progression at the end of the 5-year follow-up period. Patients who started therapy with two NRTI and a non-NRTI had the lowest likelihood of progression to AIDS or death at 5 years of follow-up. This is because, in the case of the subgroup whose initial treatment included a protease inhibitor, failure rates due to non-adherence to therapy are high and response to salvage therapy is limited by past protease inhibitor experience. CONCLUSIONS: Despite the superior virologic potency of the protease inhibitor-containing regimens, in this analysis other strategies performed equally well or even better. In the absence of solid empirical data and until the advent of antiretroviral regimens that are shown to be safe, simple to take, and maximally suppress viral load, caution may be required in selecting the long-term therapy for patients with less advanced HIV disease.

Anti-HIV Agents↗
PubMed1998

Anti-HIV coumarins from Calophyllum seed oil.

The seeds of Calophyllum cerasiferum Vesque (Family-Clusiaceae), and Calophyllum inophyllum Linn. (Family-Clusiaceae) contain several known coumarins, among which were the potent HIV reverse transcriptase inhibitors costatolide and inophyllum P. Calophyllum cerasiferum contained (-)-calanolide B as its major coumarin constituent in significant amount and thus constitute a renewable source of this compound.

Anti-HIV Agents↗
PubMed2003

Meta-analysis of randomized controlled trials of simplified versus continued protease inhibitor-based antiretroviral therapy in HIV-1-infected patients.

OBJECTIVE: To evaluate the efficacy and safety of simplified maintenance therapy (SMT) compared with continued protease inhibitor (PI) therapy. DESIGN: Meta-analysis of nine randomized controlled trials in which 833 patients were switched to SMT (abacavir, efavirenz or nevirapine) and 616 continued PI, assessing virologic failure (primary outcome), discontinuation of therapy for reasons other than virologic failure, CD4 cell count, total plasma cholesterol and triglycerides. RESULTS: The risk ratio for virologic failure for SMT compared to continued PI was 1.06 [95% confidence interval (CI) 0.58-1.92; test for homogeneity P = 0.01] for SMT, 2.56, (95% CI, 1.17-5.64) for abacavir, 0.83 (95% CI, 0.36-1.91) for efavirenz and 0.54 (95% CI, 0.29-1.02) for nevirapine. The risk ratio for premature discontinuation of therapy with SMT was 0.61 (95% CI, 0.48-0.77; test for homogeneity P < 0.10). The difference in absolute mean cholesterol for SMT compared to continued PI was -0.15 mmol/l, (95% CI, -0.40 to 0.09; test for homogeneity P < 0.01) for SMT, -0.51 mmol/l (95% CI, -0.70 to -0.33) for abacavir, 0.22 mmol/l (95% CI, 0 to 0.43) for efavirenz and -0.19 mmol/l (95% CI, -0.48 to 0.09) for nevirapine. CONCLUSIONS: Current evidence suggests that SMT with abacavir rather than continued PI increases the risk of virologic failure, this increased risk may be confined to patients with prior mono or dual therapy with reverse transcriptase inhibitors. There is not enough evidence on whether SMT with efavirenz and nevirapine influences the risk of virologic failure. SMT with any of the three drugs reduces the risk of discontinuation of therapy, and SMT with abacavir reduces plasma cholesterol.

Adult↗
PubMed2006

Short communication metabolic and mitochondrial effects of switching antiretroviral-experienced patients to enfuvirtide, tenofovir and saquinavir/ritonavir.

OBJECTIVE: Investigate the metabolic and mitochondrial effects of switching a highly active antiretroviral therapy (HAART) regimen with a high mitochondrial toxicity profile to a HAART with a theoretically low mitochondrial toxicity. PATIENTS AND METHODS: Six consecutive HAART-experienced patients receiving at least one dideoxy-nucleoside reverse transcriptase inhibitor (NRTI) switched to enfuvirtide plus tenofovir plus saquinavir/ritonavir (T20+TDF+SQV/r). Blood samples were collected at baseline, 12 and 24 weeks after the switch, and viral load (VL) and lymphocyte CD4+ T-cell count were determined. Metabolic parameters consisted of fasting serum triglycerides, cholesterol (total and fractions), glucose, insulin, C-peptide and lactate. Mitochondrial assessment consisted on mitochondrial DNA (mtDNA) quantification, COX-II mitochondrial protein expression rate, mitochondrial respiratory chain complex III and IV activities, and oxygen consumption in peripheral blood mononuclear cells. For baseline mitochondrial comparisons, we included six HIV-infected patients naive for ART. RESULTS: Switched patients exhibited a mean increase of 26 CD4+ T-cells/mm3 and a mean decrease of 1.1 log in VL (P = NS for both). Lactate, lipids and glycaemia remained stable during the study; only insulin levels increased significantly (P < 0.05). Switched patients exhibited, at baseline, low mitochondrial measurements, being significant only for complex III and IV activities with respect to naive patients (P < 0.05 for both). MtDNA content did not rise significantly during the study. However, we observed increases in COX-II mitochondrial protein synthesis (124%, P < 0.05), complex III activity (127%, P < 0.05), complex IV activity (86%, P = 0.37) and oxygen consumption (194%, P < 0.05). CONCLUSION: Switching a HAART-containing dideoxy-NRTI to T20+TDF+SQV/r minimally alters metabolic parameters and exerts beneficial effects on mitochondrial function at 24 weeks. Mitochondrial improvement should be considered as an additional advantage of this rescue therapy.

Adenine↗
PubMed2003

Recurrence of post-traumatic stress disorder symptoms after initiation of antiretrovirals including efavirenz: a report of two cases.

BACKGROUND: Some antiretrovirals has been reported to cause a wide range of psychiatric symptoms. However, reappearance of post-traumatic stress disorder (PTSD) symptoms has not been described in relation to these medications. DESIGN: Case report. SETTINGS: The Boston Medical Center, a tertiary care academic centre. FINDINGS: Two HIV-infected refugees re-experienced symptoms of PTSD after starting therapy with efavirenz (EFV) and zidovudine (ZDV). The two patients had no typical factors present to account for the PTSD exacerbation. In both patients, the symptoms of PTSD gradually subsided to baseline within the first 4 weeks of antiretroviral treatment. CONCLUSIONS: We believe that EFV, a non-nucleoside reverse transcriptase inhibitor, with ZDV, may be manifesting its known neuropsychiatric toxicities in a heretofore unreported presentation of PTSD exacerbation.

Adult↗
PubMed2006

HIV-1 drug-resistance mutations among newly diagnosed patients before scaling-up programmes in Burkina Faso and Cameroon.

We analysed whether mutations associated with resistance to antiretroviral (ARV) drugs circulate among treatment-naive HIV-1-infected individuals at a period when these drugs started to become more widely available in Africa. Overall, major resistance mutations in the pol gene, as defined by the International AIDS Society Resistance Testing-USA panel, were observed in 16 treatment-naive individuals. Eight of the 97 patients tested in Burkina Faso bore mutations conferring resistance to one drug class of ARV drugs: two to nucleoside reverse transcriptase inhibitors (NRTIs; M41L [n = 1], M41L+T69S [n = 1]), four to non-NRTIs (NNRTIs; V106A/V [n = 1] and V1081 [n = 3]) and two to protease inhibitors (PIs; L33F [n = 2]). In Cameroon, resistance mutations were identified in 8 of 102 patients: three to PIs (M461/L [n = 2], L33F [n = 1]), three to NRTIs (T69N/T [n = 1], M184V [n = 1], A62V [n = 1]) and two to NNRTIs (P236L [n = 1], V1081 [n = 1]). It is important to note that not all genotypic drug-resistance algorithms give similar interpretations to the observed mutations. Population surveillance for ARV drug resistance is required and should be included in all implementation programmes.

Adult↗
PubMed2001

Impact of clinical reverse transcriptase sequences on the replication capacity of HIV-1 drug-resistant mutants.

We have shown that the HIV-1 laboratory strain NL4-3 that contains P236L [a reverse transcriptase mutation conferring resistance to the nonnucleoside reverse transcriptase inhibitor (NRTI) delavirdine] replicates more slowly than wild-type NL4-3. Other NNRTI-resistance mutations, such as K103N and Y181C, do not reduce the replication capacity of NL4-3 as much as P236L and develop more frequently in HIV-1 isolates from patients failing delavirdine. However, a minority of patients on delavirdine therapy still have isolates with P236L. We postulated that reverse transcriptase (RT) sequences from these patient isolates contain other mutations that compensate for the adverse effect of P236L. To test this hypothesis, we created 15 chimeric NL4-3 isolates that contained delavirdine-resistant RT sequences derived from eight patient isolates and characterized their replication kinetics. Nine of 10 patient-derived clones containing P236L replicated as slowly as NL4-3 with P236L. In contrast, three of five clones that did not have P236L (but had either K103N or Y181C) replicated significantly better than NL4-3 with P236L. Thus, the majority of patients who acquire P236L during delavirdine therapy do not have RT mutations that compensate for the replication defect conferred by P236L. We hypothesize that HIV-1 isolates with P236L may have a compensatory mutation outside RT. Alternatively, variants of HIV-1 with reduced replication fitness may be selected during antiretroviral therapy, suggesting that stochastic events rather than viral replication fitness may determine which drug-resistant mutants emerge early during antiretroviral failure. In some isolates, it appears that the background RT sequence can contribute significantly to the replication fitness of drug-resistant HIV-1 variants.

Anti-HIV Agents↗
PubMed1995

Clinical significance of drug resistance in human immunodeficiency virus.

Antiretroviral drugs exert only limited activity against viruses that replicate persistently to high levels. Thus, drug-resistant viruses readily emerge. It has been difficult to assess the contribution of such drug resistance to the failure of treatment with drugs that have only limited effectiveness in the first place. The emergence of zidovudine-resistant human immunodeficiency virus is predictive of clinical disease progression, although the relationship of this event to treatment failure is particularly complicated. The relationship between drug resistance and the loss of activity of non-nucleoside reverse transcriptase inhibitors and protease inhibitors appears to be more straightforward. The optimal use of antiretroviral drugs and combination regimens requires an appreciation of the impact of drug resistance.

Acquired Immunodeficiency Syndrome↗