Characterizing Human Immunodeficiency Virus Antiretroviral Therapy Interruption and Resulting Disease Progression Using Population-Level Data in British Columbia, 1996-2015.

BACKGROUND: Suboptimal retention is among the biggest challenges to realize the full benefits of combination antiretroviral therapy (ART). We aimed to describe ART interruption patterns and identify determinants of disease progression while off ART in British Columbia, Canada. METHODS: With population-level data on ART utilization and laboratory testing in British Columbia (1996-2015), we described the timing, frequency, and duration of ART interruptions (a gap of ≥90 days in ART dispensation records). A 4-state continuous-time Markov model was implemented to identify determinants of disease progression during individuals' first ART interruption episode. Disease progression was measured according to CD4-based state transitions (cells/µL: ≥500 to 200-499; 200-499 to <200; ≥500 to death; 200-499 to death; and <200 to death). RESULTS: Among individuals initiating ART, 3129 (38.6%) interrupted ART over a median 8-year follow-up (interquartile range [IQR], 4.3-13.5 years). Those interrupting ART had a median of 1 interruption (IQR, 1.0-3.0), with the first interruption occurring 12.8 (IQR, 4.0-36.1) months after ART initiation, lasting for 7.5 (IQR, 4.1-20.3) months. The proportion of individuals interrupting ART within the first year of ART initiation decreased over time; however, the absolute number of individuals interrupting ART remained high. In a multivariable analysis, age, historical plasma viral load, and ART regimen changes prior to interruption were associated with increased hazard of CD4 decline and death. CONCLUSIONS: Our results demonstrate that ART interruptions are common even in a high-resource setting with universal free access to human immunodeficiency virus care. Further efforts are needed to promote ART reengagement and may consider prioritizing individuals with poorer prognostic factors.

Predicting hospitalization among HIV-infected antiretroviral naïve patients starting HAART: determining clinical markers and exploring social pathways.

In the era of highly active antiretroviral therapy (HAART), hospitalization as a measure of morbidity has become of increasing interest. The objectives of this study were to determine clinical predictors of hospitalization among HIV-infected persons initiating HAART and to explore the impact of gender and drug use on hospitalization. The analysis was based on a cohort of HIV-positive individuals initiating HAART between 1996 and 2001. Information on hospitalizations was obtained through data linkage with the BC Ministry of Health. Cox-proportional hazard models were used to assess variables associated with time to hospitalization. A total of 1,605 people were eligible and 672 (42%) were hospitalized for one or more days. The final multivariate model indicated that there was an increased risk of hospitalization among those with high baseline HIV RNA (HR for > 100,000 copies/mL: 1.26; 95%CI: 1.16-1.59) or low CD4 cell counts (HR [95% CI] compared to > or = 200 cells/mm3: 1.62 [1.28-2.06] and 1.29 [1.07-1.56] for < 50 and 50-199 cells/mm(3), respectively). Other factors, including adherence, previous hospitalization, gender and injection drug use remained predictive of hospitalization. These findings highlight the importance of closely monitoring patients starting therapy with low CD4 cell counts in order to mediate or prevent outcomes requiring hospitalization.

Discordances between interpretation algorithms for genotypic resistance to protease and reverse transcriptase inhibitors of human immunodeficiency virus are subtype dependent.

The major limitation of drug resistance genotyping for human immunodeficiency virus remains the interpretation of the results. We evaluated the concordance in predicting therapy response between four different interpretation algorithms (Rega 6.3, HIVDB-08/04, ANRS [07/04], and VGI 8.0). Sequences were gathered through a worldwide effort to establish a database of non-B subtype sequences, and demographic and clinical information about the patients was gathered. The most concordant results were found for nonnucleoside reverse transcriptase (RT) inhibitors (93%), followed by protease inhibitors (84%) and nucleoside RT inhibitor (NRTIs) (76%). For therapy-naive patients, for nelfinavir, especially for subtypes C and G, the discordances were driven mainly by the protease (PRO) mutational pattern 82I/V + 63P + 36I/V for subtype C and 82I + 63P + 36I + 20I for subtype G. Subtype F displayed more discordances for ritonavir in untreated patients due to the combined presence of PRO 20R and 10I/V. In therapy-experienced patients, subtype G displayed a lot of discordances for saquinavir and indinavir due to mutational patterns involving PRO 90 M and 82I. Subtype F had more discordance for nelfinavir attributable to the presence of PRO 88S and 82A + 54V. For the NRTIs lamivudine and emtricitabine, CRF01_AE had more discordances than subtype B due to the presence of RT mutational patterns 65R + 115 M and 118I + 215Y, respectively. Overall, the different algorithms agreed well on the level of resistance scored, but some of the discordances could be attributed to specific (subtype-dependent) combinations of mutations. It is not yet known whether therapy response is subtype dependent, but the advice given to clinicians based on a genotypic interpretation algorithm differs according to the subtype.

HIV type 1 BF recombinant strains exhibit different pol gene mosaic patterns: descriptive analysis from 284 patients under treatment failure.

Different complex structures of the pol gene have been identified in 284 HIV-1 B/F recombinant sequences obtained from a group of 587 patients under treatment failure from Argentina. To analyze the mosaic structures of these viral sequences and to determine their phylogenetic relationship, the 284 partial pol gene sequences of BF recombinant viruses were amplified by RT-PCR and sequenced. Intersubtype breakpoints were analyzed by bootscanning. Phylogenetic relationships were determined by means of neighbor-joining trees. The analysis of the sequences showed multiple phylogenetic topologies clustering within intersubtype BF reference sequences. At least three different mosaic patterns were found compared to previously described BF-type viruses with unequal distribution in the studied population. The analysis also showed that HIV-1 BF recombinant viruses with diverse mosaic structures are phylogenetically related in their F segments and in selected B fragments with the F1 subtype and with BF recombinant viruses from Brazil, respectively, suggesting a common recombinant ancestor. No association was observed between the prevalence of each mosaic pattern and the frequency of major drug-resistance mutations in PR and RT.

"Discordant" increases in CD4 cell count relative to plasma viral load in a closely followed cohort of patients initiating antiretroviral therapy.

BACKGROUND: In HIV-positive persons receiving antiretroviral therapy, CD4 cell responses are associated with optimal suppression of viral replication. However, increases in CD4 cell counts in the absence of viral suppression have been reported. We characterized plasma viral load (pVL) and CD4 cell count increases in closely followed patients to evaluate determinants and the prevalence of CD4 cell responses at a populational level. METHODS: All HIV-positive patients in the province of British Columbia, Canada, who were antiretroviral naive and initiated therapy between August 1996 and May 1998 were eligible for the study. The selection criteria were that patients had to have CD4 cell counts and pVLs measured at baseline and at least once during eight 16-week periods after the initiation of therapy. We characterized CD4 cell responses and sought patients who had a "discordant" increase at 1 year, which was defined as an increase in CD4 cell count of >or=50/mm3 with a <1 log10 decrease in pVL. We also evaluated adherence and antiretroviral use. RESULTS: Overall, when baseline and 1-year pVLs and CD4 cell counts were compared, 6.2% of patients had CD4 cell count increases without pVL decreases of >or=1 log10. However, when all pVLs before 1 year were considered, 92% of the discordant increases could be attributed to prior transient or partial viral suppression. Furthermore, although substantial increases in CD4 cell counts were observed in transient virologic responders, the cumulative number of antiretroviral agents used by this group was significantly higher than that used by full virologic responders (p <.001). CONCLUSIONS: Our results demonstrate that virtually all CD4 cell count increases can be attributed to transient or partial pVL suppression. Unmeasured pVL suppression likely explains discordant responses that have been previously reported. Similarities between transient and full virologic responders also appear to be time limited and are often associated with greater cumulative use of antiretroviral therapy by transient virologic responders.