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Background/Aim: The aim of this prospective study was to compare the response to alfa-interferon treatment of chronic hepatitis C in two groups of patients: coinfected with human immunodeficiency virus (HIV) (G I) or not (G II). Methods: One hundred and fifty-three patients with chronic hepatitis C had been enrolled in 30 French liver units or infectious diseases units between May 1992 and January 1995 (G I: 76, G II: 77) to receive alfa-2a interferon: 3 MU thrice weekly for 6 months. Results: One hundred and twenty-seven patients (G I: 63, G II: 64) fulfilled all criteria for analysis. The two groups were comparable for all demographic data, while significantly more severe biological and histological ( p =0.001) parameters attested to more serious hepatitis among HIV-HCV coinfected patients. HCV viremia was higher among HIV-coinfected patients ( p =0.0169), while genotype repartition was identical among the two groups (more than 52% of genotype 1, more than 31% of genotype 3). ALT normalization was, respectively, (G I/G II) obtained in 17.46%/26.56% (not significant) of patients at the end of treatment and in 11.11%/12.5% (not significant) of patients after 6 months of follow-up. In a multivariate analysis, GGT level before therapy (relative risk 2.1, confidence interval 1.1–5.8) and body surface area (relative risk 1.9, confidence interval 1.1–3.7) were the variables independently associated with the response to alfa-interferon treatment (higher GGT and more elevated body surface area were associated with a risk of non-response). Conclusion: In our study HIV infection did not affect the alfa-interferon treatment response of chronic hepatitis C, and response could be achieved among HIV-coinfected patients. Present therapeutic anti-HCV schedules need to be proposed to HIV-HCV coinfected patients before severe immunosuppression occurs. On the other hand, more severe biological and histological parameters were observed among HIV-HCV coinfected patients, which suggests a need to study whether HIV infection is associated with a worsening course of chronic hepatitis C.

We report the development of a new group of nonnucleoside reverse transcriptase inhibitors (NNRTIs). One of the most active congeners of this series of 1,1,3-trioxo-2 H ,4 H -thieno[3,4- e ][1,2,4]thiadiazine (TTD) derivatives, i.e., 2-(3-fluorobenzyl)-4-cyanomethylen-1,1,3-trioxo-2 H ,4 H -thieno[3,4- e ][1,2,4]thiadiazine) (QM96639) was found to inhibit human immunodeficiency virus (HIV) type 1 [HIV-1 (III B )] replication in MT-4 cells at a concentration of 0.09 μM. This compound was toxic for the host cells only at a 1,400-fold higher concentration. The TTD derivatives proved effective against a variety of HIV-1 strains, including those that are resistant to 3′-azido-3′-deoxythymidine (AZT), but not against HIV-2 (ROD) or simian immunodeficiency virus (SIV/MAC251). HIV-1 strains containing the L100I, K103N, V106A, E138K, Y181C, or Y188H mutations in their reverse transcriptase (RT) displayed reduced sensitivity to the compounds. Their cross-resistance patterns correlated with that of nevirapine. 2-Benzyl-4-cyanomethylen-1,1,3-trioxo-2 H ,4 H -thieno[3,4- e ][1,2,4]thiadiazine (QM96521) enhanced the anti-HIV-1 activity of AZT and didanosine in a subsynergistic manner. HIV-1-resistant virus containing the V179D mutation in the RT was selected after approximately six passages of HIV-1 (III B ) in CEM cells in the presence of different concentrations of QM96521. From structure-activity relationship analysis of a wide variety of TTD derivatives, a number of restrictions appeared as to the chemical modifications that were compatible with anti-HIV activity. Modelling studies suggest that in contrast to most other NNRTIs, but akin to nevirapine, QM96521 does not act as a hydrogen bond donor in the RT-drug complex.

Etravirine (ETR) is a next generation non-nucleoside reverse transcriptase inhibitor (NNRTI). The studies for ETR EMA approval were almost exclusively performed together with the protease inhibitor (PI) darunavir. However the fact that ETR can be active against NNRTI-pretreated HIV variants and that it is well tolerated suggests its application in PI-free antiretroviral combination therapies. Although approved only for PI-containing therapies, a number of ETR treatments without PIs are performed currently. To evaluate the performance of ETR in PI-free regimens, we analyzed the EURESIST database. We observed a total of 70 therapy switches to a PI-free, ETR containing antiretroviral combination with detectable baseline viral load. 50/70 switches were in male patients and 20/70 in females. The median of previous treatments was 10. The following combinations were detected in the EURESIST database: ETR+MVC+RAL (20.0%); ETR+FTC+TDF (18.6%); 3TC+ETR+RAL (7.1%); 3TC+ABC+ETR (5.7%); other combinations (31.4%). A switch was defined as successful when either ≤50 copies/mL or a decline of the viral load of 2 log 10 , both at week 24 (range 18-30) were achieved. The overall success rate (SR) was 77% (54/70), and for the different combinations: ETR+MVC+RAL =78.6% (11/14); ETR+FTC+TDF =92.3% (12/13); 3TC+ETR+RAL =80.0% (4/5), 3TC+ABC+ETR =100% (SR 4/4); and for other combinations =67.6% (23/34). These SR values are comparable to those for other therapy combinations in such pretreated patients. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Schuelter E et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18260 http://www.jiasociety.org/index.php/jias/article/view/18260 | http://dx.doi.org/10.7448/IAS.15.6.18260

Objective : To evaluate the immunological and virological efficacy of triple combination therapy with zidovudine (ZDV) plus zalcitabine (ddC) plus lamivudine (3TC) and a double (ZDV+3TC) combination therapy in patients previously treated with ZDV plus ddC. Design : A 6-month follow-up open-label randomized study was undertaken in 46 HIV-1-infected patients previously treated for at least 6 months with ZDV plus ddC, who were allocated to receive either ZDV/ddC/3TC (n = 15) or ZDV/3TC (n = 15) or to continue with the ZDV/ddC regimen (control group ; n = 16). Methods : Changes in CD4+ cell counts and plasma viral load (VL) were analysed with analysis of variance. Sequencing of the reverse transcriptase gene was performed in a subset of 3TC-treated patients. Results : Mean CD4+ cell counts increased significantly above baseline in both 3TC regimens whereas counts decreased in the control group. Significant plasma VL reduction was achieved in both 3TC combination therapy groups at weeks 4 and 24 compared with the control group. Coexistence of mutations conferring resistance to ZDV and 3TC were found in patients from both 3TC treatment groups. Conclusions : Both therapy strategies, switching ddC to 3TC or adding 3TC, significantly improved the virological and immunological efficacy compared with continuing ZDV/ddC. Our results support the use of 3TC in patients previously treated with the ZDV/ddC combination.

Objective : To define genotypic and phenotypic resistance patterns following prolonged therapy with the protease inhibitor ritonavir (ABT-538). Design : Seven HIV-1-infected patients, all but one previously treated with dideoxy-nucleoside analogues (zidovudine, didanosine, zalcitabine), were treated for 1 year with ritonavir. Methods : Direct solid-phase sequencing of the protease gene starting from plasma derived viral RNA followed by comparison to phenotypic drug resistance data. Results : The most frequent amino-acid substitutions occurring upon administration of the protease inhibitor were V 82 A/F (substrate binding site), I 54 V (flap region), A 71 V and L 10 I. Additional mutations found in more than one patient were I 15 V, M 36 I, I 84 V and I 93 L. Mutation L 63 P was found both in pre- and post-ritonavir samples. Phenotypic drug resistance assays confirmed resistance to ritonavir in post-treatment samples (∼170-fold) and showed cross-resistance to indinavir (∼30-fold) and partially to saquinavir (-fivefold). At 1 year of treatment, one patient without known resistance-associated mutations in the protease gene still showed a substantial rise in CD4 cell count accompanied by a more than 2.4 log decrease in RNA viral load. However, at week 78, mutations R 8 Q, E 34 K, R 57 K, L 63 P and I 84 V were detected and the treatment benefit was partially lost. Conclusions : Long-term treatment with ritonavir is associated with the emergence of multiple mutations in the HIV-1 protease gene. The mutations L 10 I, I 54 V, L 63P , A 71 V, V 82 A/F and I 84 V correspond to known drug-resistance mutations for ritonavir and other protease inhibitors. Phenotypic resistance to ritonavir was detected in a majority of ritonavir-treated patients at 1 year of treatment. In addition, long-term ritonavir treatment selects for cross-resistance to the protease inhibitors indinavir and saquinavir. This argues against sequential therapy with several protease inhibitors. Delayed resistance in one patient was accompanied with a prolonged increase in CD4 cell count and decrease in viral load suggesting a temporary benefit of treatment.