Treatment interruption in HIV-1-infected patients with multiresistant virus and limited therapeutic options may favour the overgrowth of the wild-type virus, and thus potentially lead to a better outcome after subsequent therapy [1,2]. However, in clinical trials involving patients with advanced disease, treatment interruption was associated with a significant decrease in CD4 T cells and a greater risk of disease progression [3–5], and only limited data are currently available in patients with less advanced disease [6,7]. Therefore, treatment interruption strategy is not currently recommended outside the clinical trials.
Nevertheless, patients with detectable viraemia frequently undergo treatment interruption in clinical practice [8,9], particularly if they have high CD4 T-cell counts, and such discontinuations are often the result of patient decisions based on side-effects or the fear of them, or a desire for a ‘drug holiday’ [8,9].
The M184V substitution in the HIV-1 reverse transcriptase (RT) gene develops rapidly after lamivudine monotherapy and confers high-level phenotypic drug resistance . Its presence is associated with alterations in various mechanisms relating to RT function; in-vitro studies have shown that M184V-containing HIV-1 RT is more faithful than the wild-type molecule , and that viruses harbouring the mutation replicate less efficiently [12,13]. Moreover, recent data have shown that such a virus may remain more sensitive to lamivudine than previously believed [14–16]. The continuation of lamivudine after the appearance of the M184V mutation may therefore have a positive effect on CD4 T-cell changes and clinical progression. Furthermore, as there is no evidence that lamivudine selects for any other mutation, its continuation as monotherapy is unlikely to increase HIV resistance to other antiretroviral agents.
The aim of the Experienced-184V (E-184V) study was to compare the effects of lamivudine monotherapy on 48-week immunological or clinical failure with those of complete therapy interruption in HIV-1-infected patients harbouring a lamivudine-resistant virus.
Adult HIV-1-infected patients requesting therapy interruption were recruited at the Clinic of Infectious Diseases, Vita-Salute San Raffaele University of Milan, after being appropriately counselled regarding the lack of controlled clinical trial data to support this approach, the need for close clinical and laboratory evaluation, safe sex practices to avoid HIV transmission, and the planned resumption of therapy. They were considered eligible if they had CD4 T-cell counts greater than 500 cells/μl and HIV-RNA levels greater than 1000 copies/ml, were receiving lamivudine-containing HAART, and showed the M184V mutation at genotype screening. The exclusion criteria were hepatitis B surface antigen positivity, a history of HIV-related thrombocytopenia, an active opportunistic infection, the use of immunomodulants or cytotoxic chemotherapeutic agents in the previous 6 months, and pregnancy or the wish to become pregnant. The study was approved by the Institutional Ethical Committee in August 2002, and all patients gave their written informed consent. Recruitment began in October 2002 and was completed in March 2004.
This was a prospective, randomized (1: 1), open-label, parallel-group, 48-week pilot study. The patients were randomly assigned to stop all antiretroviral drugs (TI group) or to continue receiving lamivudine alone (lamivudine group) on the basis of a computer-generated list prepared by our statistician and stratified by CD4 T-cell counts (≤ 700/> 700 cells/μl). The primary study endpoint was the occurrence of immunological or clinical failure. Immunological failure was defined as the first report of a CD4 T-cell count of less than 350 cells/μl (subsequently confirmed within 2 weeks), and clinical failure as the occurrence of a Centers for Disease Control and Prevention (CDC) grade B or C event. In either case, the patients had to discontinue the study and resume a HAART regimen based on the results of the baseline resistance test.
The secondary endpoints were the time to immunological or clinical failure, the frequency of adverse events and haematological or biochemical abnormalities, changes from baseline in CD4 T-cell counts, CD4 cell percentage, CD8 T-cell counts, CD8 cell percentage, plasma HIV-RNA levels, the number of drug resistance mutations, viral replication capacity (RC), and the 24-week virological and immunological response to the subsequent HAART regimen.
Assessment and monitoring
The patients were evaluated at screening, baseline, every 4 weeks until week 24, and then every 12 weeks until week 48, or at study discontinuation; the patients resuming therapy were followed up for 24 weeks. At each visit, an interim history was taken and a complete physical examination was performed by the study investigators. Adverse events were recorded as they occurred, graded 1–4 according to the DAIDS grading system, and adjudged related or not to HIV-1. Fasting haematological and blood chemistry evaluations were performed at each timepoint, as were CD4 and CD8 T-cell counts (cells/μl), and plasma HIV-RNA determinations (copies/ml). HIV-1 genotyping was performed at screening, baseline, and then every 12 weeks until week 48 or study discontinuation; RC was measured at baseline, week 24 and week 48, or at discontinuation.
Viral load and sequence analysis
Viral RNA was quantified in plasma using the Versant HIV-1RNA Assay (branched DNA; Bayer Health Care, Tarrytown, New York, USA), with a lower quantitation limit of 50 copies/ml.
The HIV-1 pol gene was sequenced by means of HIV-RNA extraction using the QIAmp viral RNA kit (Qiagen GmbH, Hilden, Germany). The RNA was reverse-transcribed to complementary DNA using Expand Reverse Transcriptase (Hoffman-LaRoche, Mannheim, Germany), and the cDNA was amplified by means of two nested reactions using the Expand High Fidelity polymerase chain reaction system kit (Hoffman-LaRoche) and oligonucleotide primers (Virco, Mechelen, Belgium). The amplified fragments were purified using the QIAquick kit (Qiagen), and sequenced using Megabace 1000 (Pharmacia–Amersham, Freiburg, Germany). Only the mutations known to be associated with drug resistance were considered ; wild-type virus was defined by the absence of any of these mutations.
Viral replication capacity
HIV-1 genomic RNA was purified from the plasma of the study subjects at baseline, week 24 and week 48, or discontinuation (QIAmp RNA kit; Qiagen), reverse transcribed, and amplified using PWO DNA polymerase (Roche, Zurich, Switzerland); primers proteases, 5′–TCA AAT CAC TCT TTG GCA ACG and reverse transcriptases, 5′–CAT GTA CTG GTT CTT TTA GAA TRTC. The amplified products were purified, restricted using heat-inactivated Agel, and added to a ligation reaction containing 10 U of T4 DNA ligase (Promega, Madison, Wisconsin, USA), together with 25 ng of the SmaI/AgeI predigested vector pΔpro described elsewhere [18,19]. The competent cells (JM109; Promega) were transformed using the heat shock technique, and the single colonies were screened by polymerase chain reaction. The plasmids were extracted using a miniprep kit (Promega), and the inserts and their junctions were verified by sequencing. Thirty nanograms of each HIV-1 molecular clone recombinant for the pr–rt region were transfected into U87 cells (transgenic for CD4 and CXCR4) in round-bottomed, 96-well plates using Lipofectin reagent (Invitrogen, Carlsbad, California, USA). The clones relating to the baseline and 48-week samples of each subject were always transfected in the same experimental session, and the wells were incubated in medium for 4 days. P24 antigen (p24Ag) was quantified in the supernatants by an immunoenzymatic assay (Du Pont, Wilmington, Delaware, USA). The RC of each clone was defined as the p24Ag production (ng/ml) by each recombinant clone after 4 days in culture, and the samples taken at weeks 24 and 48 (or study discontinuation) were compared with the baseline samples using the ratios RC24 or study discontinuation/RCbaseline and RC48 or study discontinuation/RCbaseline.
As this was an exploratory proof-of-concept (pilot) study, no formal power calculations were made, and the sample size was based on a retrospective analysis of our database and feasibility resources.
The intention-to-treat principle was applied in the analyses. In the primary endpoint analysis, discontinuations for reasons other than immunological or clinical failure were not considered as failures. For the secondary endpoints analyses, the last observation carried forward technique was applied.
The HIV-RNA values were log-transformed, and the absolute (or relative) changes between baseline and week 48 were calculated. All baseline values are medians (interquartile range; IQR) or frequencies (%) as appropriate; the changes from baseline are expressed as mean values (± SE) or medians (IQR).
The proportions of immunological or clinical failure were calculated, and their 95% confidence interval (CI) was estimated according to the modified Wald method.
The Kaplan–Meier method was used to estimate the probability of immunological or clinical failure, and the 25th (Q1) and 50th percentile (median) of the time to immunological or clinical failure.
The non-parametric Mann–Whitney rank sum test was used to compare the mean independent values of continuous variables; the chi-square or Fisher's exact test was used to assess significant relationships between discrete variables.
All of the statistical tests were two-sided at the 5% level, and performed using SAS Software, release 8.2 (SAS Institute, Cary, North Carolina, USA).
Sixty patients were enrolled, but as one patient in each arm refused the allocated treatment, the analysis was based on the 48-week results observed in the 58 evaluable patients, 29 in each group.
The baseline characteristics of the two study groups were not statistically different, with the exception of the CD4 cell percentages, which were higher in the TI group (P = 0.0501). Previous antiretroviral drug exposure was balanced: 24 of 58 patients (41.4%: 13 in the TI group versus 11 in the lamivudine group) were receiving a nucleoside reverse transcriptase inhibitor(NRTI)-based regimen, 13/58 (22.4%: six versus seven) a non-nucleoside reverse transcriptase inhibitor(NNRTI)-based regimen, and 21/58 (36.2%: 10 versus 11) a protease inhibitor (PI)-based regimen (Table 1).
A total of 21 out of 29 patients (72%) in the TI group and 13 out of 29 (45%) in the lamivudine group had discontinued the study by week 48 (P = 0.061). Two patients discontinued for reasons other than immunological or clinical failure (one TI patient withdrew his consent, one lamivudine patient died in a working accident). Treatment failures were thus 20 of 29 patients (69%; 95% CI 51–83%) in the TI group (17 immunological failures, two clinical, and one both) and 12 of 29 patients (41%; 95% CI 26–59%) in the lamivudine group (11 immunological failures and one clinical; P = 0.064).
Among the patients with baseline CD4 T-cell counts of 700 cells/μl and less, immunological or clinical failures occurred in 19 of 24 (79%) in the TI group and in 12 of 23 (52%) in the lamivudine group; the corresponding figures among the patients with baseline CD4 T-cell counts of more than 700 cells/μl were one out of five (20%) and none out of six (0%).
Among the patients with nadir CD4 cell counts of over 200 cells/μl, failures occurred in 13 out of 20 TI patients (65%) and eight out of 25 lamivudine patients (32%; P = 0.037); among the patients with nadir counts of 200 cells/μl and less, they occurred in seven out of nine TI patients (78%) and all four lamivudine patients (100%; P = 0.461).
Clinical failure occurred in three of 29 patients (10%) in the TI group; two moved from CDC group A to group B during the study (one developed pelvic inflammatory disease after 12 weeks, and the other, who also experienced immunological failure, developed oral candidiasis after 20 weeks); and the third moved from CDC group B to group C having developed oesophageal candidiasis after 38 weeks. The one clinical failure in the lamivudine group (one of 29, 3%) was an episode of oral candidiasis after 48 weeks of lamivudine monotherapy in a patient belonging to CDC group B at baseline.
Time to immunological/clinical failure
The estimated probability of immunological/clinical failure was different between the two groups (P = 0.018; Fig. 1). The median time to failure was 20 weeks in the TI group, with 25% (Q1) of the patients failing within 16 weeks; in the lamivudine group, 25% (Q1) of the patients failed within 36 weeks, but no median time to failure can be estimated because only 41% of the patients failed.
Over the study period, grade 3–4 clinical adverse events that were judged by the investigators as being at least possibly HIV-1 related occurred in six out of 29 patients (20.7%) in the TI group [acute retroviral syndrome (n = 1), pelvic inflammatory disease (n = 1), bacterial pneumonia (n = 2), oesophageal candidiasis (n = 1), Hodgkin's lymphoma (n = 1)] and in none in the lamivudine group (P = 0.02).
Grade 3–4 clinical adverse events judged as not related to HIV-1 occurred in three patients in the TI group (one carotid stenosis, one hepatitis A virus hepatitis, one myocardial infarction) and in two patients in the lamivudine group (one carotid stenosis, one accidental death). The only recorded grade 3–4 laboratory abnormality was increased transaminase levels in the patient who developed acute hepatitis A virus hepatitis.
Immunological and virological findings
Fig. 2 shows the mean changes (± SE) in CD4 T-cell counts, CD4 cell percentage and viral load from baseline to each timepoint. In Table 2 are shown the absolute variations in all of the considered variables at week 48 by treatment group.
The frequencies of NRTI and PI mutations at baseline and week 48 or discontinuation are, respectively, shown in Fig. 3 and Fig. 4.
The median (IQR) number of mutations at baseline was seven (five to 11) in the TI group and eight (six to 10) in the lamivudine group (P = 0.612); the corresponding numbers of mutations associated with resistance to NRTI, NNRTI and PI were, respectively, four (three to five), one (zero to one) and two (one to six), and five (four to five), one (zero to one) and three (one to six), with no significant between-group differences (P = 0.602, P = 0.385 and P = 0.941, respectively).
At week 48 or discontinuation, the mean decrease in the number of mutations was 6.8 ± 0.86 in the TI group, and 2.6 ± 0.56 in the lamivudine group (P = 0.0003). At week 48 or discontinuation, the wild-type virus overgrew in nine of 29 patients (31%) in the TI group. The M184V mutation disappeared in all but one of the patients in the TI group (who discontinued the study at week 8), and was maintained by all of the patients in the lamivudine group.
RC measurements are available for the first 28 patients enrolled in the study (13 in the TI and 15 in the lamivudine group). Median baseline RC was 474 (110–1680) ng/ml in the TI group, and 760 (312–1750) ng/ml in the lamivudine group without significant differences (P = 0.306). Fig. 5 shows RC recovery in both groups during the study.
Response to subsequent therapy
All of the 12 lamivudine patients and 19 of 20 TI patients experiencing immunological/clinical failure resumed HAART and were followed up for at least 24 weeks; the remaining failing patient in the TI group refused to resume therapy. The HAART was based on the genotyping performed at baseline, and all of the patients received a regimen that included two NRTI (excluding lamivudine) and one PI (mainly lopinavir/ritonavir). Treatment regimens were balanced between the two groups.
At the time of HAART resumption, there were still no significant between-group differences in median (IQR) CD4 T-cell counts [313 (243–372) versus 302 (247–347) cells/μl, P = 0.892] or CD4 cell percentage [20.0% (17.2–22.3) versus 19.0% (14.3–24.7), P = 0.876], but the HIV-RNA level was significantly higher in the TI group; 4.94 (4.74–5.33) versus 4.35 (4.23–4.87) log10 copies/ml (P = 0.002). At the same time, the median (IQR) number of mutations associated with resistance to NRTI, NNRTI and PI was, respectively, zero (zero to one), zero (zero to zero) and one (zero to two) in the TI group, and four (two to five), zero (zero to one) and three (one to six) in the lamivudine group (P < 0.0001, P = 0.028, P = 0.023).
Twenty-four weeks after the resumption of HAART, the mean changes in CD4 T-cell count, CD4 cell percentage and HIV-RNA level were, respectively, 183 ± 44 cells/μl, 3.41 ± 1.48% and −2.14 ± 0.33 log10 copies/ml in the TI group, and 209 ± 54 cells/μl, 2.92 ± 1.34% and −2.07 ± 0.35 log10 copies/ml in the lamivudine group (P = 0.919, P = 0.516, P = 0.605 for CD4 T cells, CD4 cell percentage and HIV-RNA level, respectively).
Eight of the 19 patients (42%) in the TI group and nine of the 12 (75%) in the lamivudine group had plasma HIV-RNA levels of less than 50 copies/ml. One TI patient developed herpes zoster 16 weeks after resuming HAART.
In this 48-week pilot study, CD4 cell-guided therapy interruption in HIV-1-infected patients with high CD4 T-cell counts and detectable viraemia led to immunological/clinical failure in more than 70% of cases after a median of 20 weeks, disease progression occurred in 10%, and grade 3–4 adverse events at least possibly related to HIV-1 viral replication occurred in 20%, whereas continuing lamivudine led to less frequent (41%) and significantly delayed immunological/clinical failure, with none of the patients experiencing disease progression or grade 3–4 HIV-1-related adverse events during the same period.
In comparison with therapy interruption, lamivudine monotherapy induced a non-significantly smaller decrease in the absolute number of CD4 T cells and a significantly decrease in the CD4 cell percentage. This discrepancy may be explained by the reduced variability over time of CD4 cell percentages in comparison with the absolute CD4 cell number [20–22].
Furthermore, the patients receiving lamivudine experienced a significantly lower viral rebound. The re-emergence of a more sensitive virus was clearly evident in the TI group, although, consistently with previous studies, a shift to a complete wild-type virus at 48 weeks or at the time of study discontinuation was observed in only approximately 30% of the patients undergoing complete therapy interruption [4,6]. It is interesting to note that none of the patients in the lamivudine group selected further mutations, which suggests that this approach would not compromise future therapeutic options. In line with their genotype evolution, the RC of the virus recovered from the patients receiving lamivudine was 10 times less than that observed in patients undergoing therapy interruption. It is still unclear whether the lower viral rebound observed with the continuation of lamivudine can be attributed to the direct residual antiviral activity of nucleoside analogues against resistant virus [14–16], the maintenance of the M184V mutation [12,13], or both.
Our hypothesis is that, together with the maintenance of the M184V mutation, the reduced viral RC observed in the lamivudine group may have played a direct role in slowing the decline in CD4 T cells. Previous studies have shown that patients recently infected with a virus with a low pol RC had significantly higher CD4 T-cell counts regardless of drug resistance and plasma HIV-1-RNA levels , and that pol RC independently influences the natural history of HIV infection in patients with haemophilia .
We found a similar 24-week virological response after therapy resumption in both groups, despite the persistence of a higher number of mutations in the lamivudine group and the similarity of the regimens given to the patients at the time of HAART resumption. The impact of the lower viral load observed in the lamivudine group at the time of HAART resumption in favouring the positive outcome in this group needs to be investigated further.
The limitations of our study include the fact that the lack of previous efficacy and safety data meant that it was designed to be a pilot study, and included heavily pretreated patients with detectable viraemia and high CD4 T-cell counts who requested therapy interruption. Therefore, the external validity of this approach in the general HIV population is still unknown and needs further investigation. Nevertheless, lamivudine monotherapy could be considered in patients with multidrug resistance in whom ‘waiting’ for the availability of at least two active drugs may once again make the achievement of virus undetectability a reasonable goal.
In conclusion, our results indicate that, in patients harbouring a lamivudine-resistant virus, lamivudine monotherapy may lead to better immunological and clinical outcomes than complete therapy interruption, without compromising subsequent treatment options.
A.C., A.L. and A.D. wrote the E-184V study protocol. A.C., A.D., N.G., M. Cernuschi and H.H. followed the patients, E.C. was the study coordinator, L.G. did the statistical analyses, E.B. did the genotypes, A.G. did sample management and storage, and S.M. did the RC assay with advice from M. Clementi. A.C. developed the concept of this report and wrote the first draft. All the authors contributed to the final text.
Conflict of interest
A.C. has received travel support, grants or consultancy fees from Abbott, Bristol-Myers Squibb (BMS), Glaxo-SmithKline (GSK), Gilead Sciences, Pfizer, Janssen-Cilag, Roche and Tibotec. A.D. has received travel grants, grants or honoraria from BMS, GSK, Gilead Sciences, Serono and Roche. N.G. is the recipient of support for research and educational programmes from BMS, GSK, Gilead Sciences, Roche and Virco. M. Cernuschi has received travel grants or fees or honoraria from Abbott, Bayer, BMS, GSK, Gilead Sciences, Pfizer, Roche and MSD. H.H. has received travel grants or fees from Abbott, BMS, GSK, Gilead Sciences, Pfizer, Roche and MSD. A.L. has received grants, travel grants, consultancy fees from Abbott, BMS, GSK, Gilead Sciences, Pfizer, Janssen-Cilag, MSD, Roche and Tibotec. S.M., L.G., E.C., E.B., A.G. and M. Clementi have no conflicts of interest to declare.
The authors are indebted to the patients enrolled in this study, and would also like to thank Elisabetta Riva, Giuliana Fusetti and Alba Bigoloni for their invaluable technical assistance, Priscilla Biswas for critically reviewing the manuscript, and Glaxo-SmithKline for providing lamivudine.
Sponsorship: This study was supported by grants from the Fondazione San Raffaele del Monte Tabor and from the Istituto Superiore di Sanità (progetto AIDS N30S12, N 40S27).
1. Deeks SG, Grant RM, Wrin T, Paxinos EE, Liegler T, Hoh R, et al
. Persistence of drug-resistant HIV
-1 after a structured treatment interruption
and its impact on treatment response. AIDS 2003; 17:361–370.
2. Katlama C, Dominguez S, Gourlain K, Duvivier C, Delaugerre C, Legrand M, et al
. Benefit of treatment interruption
-infected patients with multiple therapeutic failures: a randomized controlled trial (ANRS 097). AIDS 2004; 18:217–226.
3. Deeks SG, Vrin BS, Liegler T, Hoh R, Hayden M, Barbour JD, et al
. Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV
-infected patients with detectable viremia. N Engl J Med 2001; 344:472–480.
4. Lawrence J, Mayers DL, Hullsiek KH, Collins G, Abrams DI, Reisler RB, et al
. Structured treatment interruption
in patients with multidrug-resistant human immunodeficiency virus. N Engl J Med 2003; 349:837–846.
5. Ghosn J, Winden M, Ktorza N, Peytavin G, Ait-Mohand H, Schneider L, et al
. No benefit of a structured treatment interruption
based on genotypic resistance in heavily pretreated HIV
-infected patients. AIDS 2005; 19:1643–1647.
6. Ruiz L, Ribera E, Bonjoch A, Romeu J, Martinez-Picado J, Paredes R, et al
. Role of structured treatment interruption
before a 5-drug salvage antiretroviral regimen: the Retrogene Study. J Infect Dis 2003; 188:977–985.
7. Antinori A, Cingolani A, Perno CF. Structured treatment interruption
-infected patients failing on multidrug therapy: is there a future for this strategy? AIDS 2005; 19:1691–1694.
8. d'Arminio Monforte A, Cozzi-Lepri A, Phillips A, De Luca A, Murri R, Mussini C, et al
. Interruption of highly active antiretroviral therapy in HIV
clinical practice: results from the Italian Cohort of antiretroviral-naive patients. J Acquir Immune Defic Syndr 2005; 38:407–416.
9. Li X, Margolick JB, Conover CS, Badri S, Riddler SA, Witt MD, Jacobson LP. Interruption and discontinuation of highly active antiretroviral therapy in the multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr 2005; 38:320–328.
10. Schuurman R, Nijhuis M, van Leeuwen P, Schipper P, de Jong D, Collis P, et al
. Rapid changes in human immunodeficiency virus type 1 RNA load and appearance of drug-resistant virus population in persons treated with lamivudine (3TC). J Infect Dis 1995; 171:1411–1419.
11. Wainberg MA, Drosopoulos WC, Salomon H, Hsu M, Borkow J, Parniak M, et al
. Enhanced fidelity of 3TC-selected mutant HIV
-1 reverse transcriptase. Science 1996; 271:1282–1285.
12. Lu J, Kuritzskes DR. A novel recombinant marker virus assay for comparing the relative fitness of HIV
-1 reverse transcriptase variants. J Acquir Immune Defic Syndr 2001; 27:7–13.
13. Wei X, Liang C, Gotte M, Wainberg MA. The M184V mutation
-1 reverse transcriptase reduces the restoration of wild-type replication by attenuated viruses. AIDS 2002; 16:2391–2398.
14. Quan Y, Brenner BG, Oliveira M, Wainberg MA. Lamivudine can exert a modest antiviral effect against human immunodeficiency virus type 1 containing the M184V mutation
. Antimicrob Agents Chemother 2003; 47:747–754.
15. Eron JJ Jr, Bartlett JA, Santana JL, Bellos NC, Johnson J, Keller A, Kuritzkes DR. Persistent antiretroviral activity of nucleoside analogues after prolonged zidovudine and lamivudine therapy as demonstrated by rapid loss of activity after discontinuation. J Acquir Immune Defic Syndr 2004; 37:1581–1583.
16. Campbell TB, Shulman NS, Johnson SC, Zolopa AR, Young RK, Bushman I, et al
. Antiviral activity of lamivudine in salvage therapy
for multidrug-resistant HIV
-1 infection. Clin Infect Dis 2005; 41:236–242.
17. Johnson VA, Brun-Vezinet F, Clotet B, Conway B, Kuritzkes DR, Pillay D, et al
. Update of drug resistance mutations in HIV
-1:2005. Top HIV
Med 2005; 13:51–57.
18. Menzo S, Rusconi S, Monachetti A, Colombo MC, Violin M, Bagnarelli P, et al
. Quantitative evaluation of the recombinant HIV
-1 phenotype to protease inhibitors by a single-step strategy. AIDS 2000; 14:1101–1110.
19. Menzo S, Monachetti A, Balotta C, Corvasce S, Rusconi S, Paolucci S, et al
. Processivity and drug-dependence of HIV
-1 protease: determinants of viral fitness in variants resistant to protease inhibitors. AIDS 2003; 17:663–671.
20. Goicoechea M, Haubrich R. CD4 lymphocyte percentage versus absolute CD4 lymphocyte count in predicting HIV
disease progression: an old debate revisited. J Infect Dis 2005; 192:945–947.
21. Burcham J, Marmor R, Dubin M, Tindall B, Cooper DA, Berry G, Penny R. CD4% is the best predictor of development of AIDS in a cohort of HIV
-infected homosexual men. AIDS 1991; 5:365–372.
22. Hulgan T, Raffanti S, Kheshti A, Blackwell RB, Rebeiro PF, Barkanic G, et al
. CD4 lymphocyte percentage predicts disease progression in HIV
-infected patients initiating highly active antiretroviral therapy with CD4 lymphocytes counts > 350 lymphocytes/mm3
. J Infect Dis 2005; 192:950–957.
23. Barbour JD, Hecht FM, Wrin T, Segal MR, Ramstead CA, Liegler TJ, et al
. Higher CD4+ T cell counts associated with low viral pol replication capacity
among treatment naive adults in early HIV
–1 infection. J Infect Dis 2004; 190:251–256.
24. Daar ES, Kesler KL, Wrin T, Petropoulo CJ, Bates M, Lail A, et al
-1 pol replication capacity
predicts disease progression. AIDS 2005; 19:871–877.
Keywords:© 2006 Lippincott Williams & Wilkins, Inc.
HIV; lamivudine monotherapy; M184V mutation; replication capacity; salvage therapy; treatment interruption