Prevalence of antiretroviral drug resistance in the HIV-1-infected urban indigent population in San Francisco: a representative study.

We determined the prevalence of antiretroviral (ARV) resistance in HIV-1 infected indigent persons in San Francisco, California. Three hundred and twenty-seven subjects (159 (49%) ARV naïve, and 168 (51%) ARV-experienced), were recruited during 1996-97 and 1999-2000. Plasma HIV-1 viral load quantification and genotypic resistance testing were performed. Twice as many subjects received nucleoside reverse transcriptase inhibitors (NRTIs) as non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs); resistance mutation prevalences were 30%, 14% and 16% respectively. Risk of any resistance mutations was strongly and independently associated with prior ARV exposure (OR = 1.3 per year of exposure, P < 0.0001) and with ARV exposure prior to HAART (OR = 2.5, P = 0.015). Prevalences of primary ARV resistance mutations among both treatment-naive and treatment-experienced subjects in this indigent urban population are low compared to other observational cohorts, are directly related to length and type of prior ARV exposure, and did not increase significantly between recruitment periods.

Characterization of the HIV-1 specific humoral immune response during highly active antiretroviral therapy (HAART).

Plasma samples from 19 patients were analyzed for HIV-1 directed humoral immune responses prior to and 1 year after initiation of HAART. Eight of the subjects were classified as virologic successes, defined by a >100-fold decrease in viral load (VL) over the 1-year study period and a final VL <500 copies/ml. The eleven HAART failures were defined as subjects with <10-fold decrease in VL. At study entry (before HAART), VL and CD4 counts were similar between the two groups. Humoral immune responses before therapy and after 1 year of therapy were measured by V3 peptide antibody binding titers and neutralization of HIV-1 MN and four subtype B clinical isolates. Before HAART, neutralizing antibody titers to the clinical isolates and HIV(MN), as well as HIV V3 envelope binding titers to several V3 peptides, were significantly higher among treatment successes compared with treatment failures. After 1 year on HAART, neutralization declined in titer and narrowed in specificity among the HAART successes. In contrast, a significant increase in both neutralizing titer and breadth was seen among HAART failures.

Genotypic correlates of a virologic response to stavudine after zidovudine monotherapy.

Prior evidence suggests that resistance to zidovudine (ZDV) confers some degree of cross-resistance to stavudine (d4T), but no genotypic correlates of clinical d4T susceptibility and resistance exist. To identify the genotypic correlates of a virologic response to d4T, reverse transcriptase (RT) sequencing of archived plasma HIV isolates was performed on 31 subjects who received d4T monotherapy in the AIDS Clinical Trials Group 302 study, all of whom received more than 3 years of ZDV monotherapy. Baseline characteristics and all RT mutations were analyzed for impact on virologic suppression. Eight of 31 subjects (27%) achieved a virologic response of greater than 0.3 log reduction in plasma HIV RNA after 8 weeks of d4T. Responders were more likely to have lower median baseline viral loads (4.2 vs. 4.7; p =.01) and a trend toward fewer ZDV-associated mutations (median: 1 vs. 2; p =.09). No subject with greater than one ZDV mutation had a virologic response to d4T. Seven of the 8 responders had only a K70R mutation at baseline. We conclude that in patients with prior ZDV treatment, those with only one ZDV mutation, particularly at position 70, can still get reasonable virologic activity from d4T. Those with more mutations are not likely to have much benefit.

Phenotypic hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in treatment-experienced HIV-infected patients: impact on virological response to efavirenz-based therapy.

BACKGROUND: Enhanced susceptibility to non-nucleoside reverse transcriptase inhibitors (NNRTI) was recently described in association with increased resistance to nucleoside analogs (nucleoside reverse transcriptase inhibitors; NRTI). OBJECTIVES: To determine the prevalence of NNRTI hypersusceptibility, the genotypic correlates, and its impact on virologic response to efavirenz-based salvage therapy. METHODS: Genotype and phenotype testing was performed retrospectively on baseline isolates from 30 patients who received salvage therapy containing efavirenz. NNRTI hypersusceptibility was defined as a 50% inhibitory concentration (IC(50)) of < 0.5 that of the wild-type control. RESULTS: Eight isolates had major NNRTI mutations. Among the 22 isolates with no major NNRTI mutations, 11 (50%) were hypersusceptible to efavirenz, 10 (45%) to delavirdine, and eight (36%) to nevirapine. Among eight isolates with NNRTI mutations, NNRTI resistance was present, but at lower than expected levels. The number of NRTI mutations was correlated inversely with the fold decrease in susceptibility to efavirenz (Spearman's rho, -0.57; P = 0.005), delavirdine (rho, -0.43; P = 0.04), and nevirapine (rho, -0.69; P < 0.001). Excluding subjects with NNRTI mutations, subjects with efavirenz hypersusceptibility at baseline had significantly better virologic suppression over 24 weeks than those without efavirenz hypersusceptibility (P < 0.001). CONCLUSION: NNRTI hypersusceptibility is common in heavily treated but NNRTI naive patients and is related directly to NRTI resistance mutations. Among patients receiving efavirenz-containing regimens, NNRTI hypersusceptibility was associated with an improved virologic outcome after 24 weeks of therapy. A reversal of phenotypic resistance was seen in patients with NNRTI mutations in the presence of multiple NRTI mutations, but no obvious virologic benefit of this phenomenon was seen in this study.

High degree of interlaboratory reproducibility of human immunodeficiency virus type 1 protease and reverse transcriptase sequencing of plasma samples from heavily treated patients.

We assessed the reproducibility of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and protease sequencing using cryopreserved plasma aliquots obtained from 46 heavily treated HIV-1-infected individuals in two laboratories using dideoxynucleotide sequencing. The rates of complete sequence concordance between the two laboratories were 99.1% for the protease sequence and 99.0% for the RT sequence. Approximately 90% of the discordances were partial, defined as one laboratory detecting a mixture and the second laboratory detecting only one of the mixture's components. Only 0.1% of the nucleotides were completely discordant between the two laboratories, and these were significantly more likely to occur in plasma samples with lower plasma HIV-1 RNA levels. Nucleotide mixtures were detected at approximately 1% of the nucleotide positions, and in every case in which one laboratory detected a mixture, the second laboratory either detected the same mixture or detected one of the mixture's components. The high rate of concordance in detecting mixtures and the fact that most discordances between the two laboratories were partial suggest that most discordances were caused by variation in sampling of the HIV-1 quasispecies by PCR rather than by technical errors in the sequencing process itself.

Highly active antiretroviral therapy results in HIV type 1 suppression in lymph nodes, increased pools of naive T cells, decreased pools of activated T cells, and diminished frequencies of peripheral activated HIV type 1-specific CD8+ T cells.

This study examines sequential lymph nodes from 13 drug-naive patients before and after 24 weeks of highly active antiretroviral therapy (HAART). A multipronged approach was used to study changes in HIV-1 RNA in each paired lymph node in relation to tissue architecture and frequency of naive T cells. After 24 weeks, all patients showed significant suppression of plasma viral load and 12 of 13 showed concordant viral suppression in the lymph node (p = 0.001). Using in situ hybridization and quantitative image analysis, we showed that HIV-1 RNA was reduced to below detectable levels (two copies per cell) in follicular dendritic cell (FDC) and mononuclear cell pools. Independent immunohistochemical analysis of lymph node sections revealed that 5 of 13 patients displayed increased FDC networks and 6 of 13 showed no change and all patients showed increases in tissue-resident CD4+ cells. All lymph node biopsies at 24 weeks showed increased proportions of CD4+ and CD8+ cells coexpressing the naive markers CD45RA and CD62L when compared with baseline values. Significant correlations existed between viral load suppression and loss of activated CD8+ T cells after 24 weeks in both lymph node and blood, which was mirrored by significantly lowered frequencies of activated peripheral Gag peptide/MHC tetramer+ CD8+ cells. Overall, these data show that a potent and successful treatment strategy that significantly suppresses and removes FDC-resident HIV-1 results in improvements in lymphoid architecture and by so doing provides the structures available for increased numbers of naive cells to interact with cognate antigen. In addition, our article shows that suppression of HIV-1 replication results in diminished frequencies of peripherally activated antigen-specific CD8+ cells.

Efavirenz- and adefovir dipivoxil-based salvage therapy in highly treatment-experienced patients: clinical and genotypic predictors of virologic response.

OBJECTIVE: To determine the impact of prior nonnucleoside reverse transcriptase inhibitor (NNRTI) therapy, genotypic resistance, and other variables on response to efavirenz (EFV)- and adefovir dipivoxil (ADV)-based salvage therapy. DESIGN: Retrospective clinical cohort study. SETTING: One university and one community-based HIV clinic. STUDY SUBJECTS: All 33 patients who were coenrolled in both the EFV and ADV expanded access programs. INTERVENTIONS: Patients received EFV 600 mg/day and ADV 120 mg/day in addition to other antiretroviral agents. OUTCOME MEASURE: HIV viral load (<500 copies/ml) at 12 and 24 weeks. RESULTS: 10 of 33 (30%) patients at 12 weeks and 8 of 33 (24%) patients at 24 weeks had viral loads <500 copies/ml. Prior NNRTI use and a history of any NNRTI-associated mutations predicted failure. Patients with Y181C or G190A single mutations had an initial greater magnitude of viral load suppression than those with K103N, but this advantage was short lived. No one with any NNRTI mutations responded with a viral load <500 copies/ml at 12 or 24 weeks. CONCLUSIONS: EFV/ADV-based salvage yielded viral load suppression at 24 weeks in 42% (8 of 19) of patients who were highly NRTI and protease inhibitor experienced but NNRTI naive. NNRTI-experienced study subjects had a poor response regardless of the specific NNRTI resistance mutation they harbored.

The relation between baseline HIV drug resistance and response to antiretroviral therapy: re-analysis of retrospective and prospective studies using a standardized data analysis plan.

To assess the relation between resistance to antiretroviral drugs for treatment of HIV-1 infection and virological response to therapy, results from 12 different studies were re-analysed according to a standard data analysis plan. These studies included nine clinical trials and three observational cohorts. The primary end-point in our analyses was virological failure by week 24. Baseline factors that were investigated as predictors of virological failure were plasma HIV-1 RNA, the number and type of new antiretroviral drugs in the regimen, and viral susceptibility to the drugs in the regimen, determined by genotyping or phenotyping methods. These analyses confirmed the importance of both genotypic and phenotypic drug resistance as predictors of virological failure, whether these factors were analysed separately or adjusted for other baseline confounding factors. In most of the re-analysed studies, the odds of virological failure were reduced by about twofold for each additional drug in the regimen to which the patient's virus was sensitive by genotyping methods, and by about two- to threefold for each additional drug that was sensitive by phenotyping.

Adherence to protease inhibitors, HIV-1 viral load, and development of drug resistance in an indigent population.

OBJECTIVE: To examine the relationship between adherence, viral suppression and antiretroviral resistance in HIV-infected homeless and marginally housed people on protease inhibitor (PI) therapy. DESIGN AND SETTING: A cross-sectional analysis of subjects in an observational prospective cohort systematically sampled from free meal lines, homeless shelters and low-income, single-room occupancy (SRO) hotels. PARTICIPANTS: Thirty-four HIV-infected people with a median of 12 months of PI therapy. MAIN OUTCOMES: Adherence measured by periodic unannounced pill counts, electronic medication monitoring, and self-report; HIV RNA viral load; and HIV-1 genotypic changes associated with drug resistance. RESULTS: Median adherence was 89, 73, and 67% by self-report, pill count, and electronic medication monitor, respectively. Thirty-eight per cent of the population had over 90% adherence by pill count. Depending on the measure, adherence explained 36-65% of the variation in concurrent HIV RNA levels. The three adherence measures were closely related. Of 20 genotyped patients who received a new reverse transcriptase inhibitor (RTI) when starting a PI, three had primary protease gene substitutions. Of 12 genotyped patients who received a PI without a new RTI, six had primary protease gene substitutions (P < 0.03). CONCLUSION: A substantial proportion of homeless and marginally housed individuals had good adherence to PI therapy. A strong relationship was found between independent methods of measuring adherence and concurrent viral suppression. PI resistance was more closely related to the failure to change RTI when starting a PI than to the level of adherence.

Adherence to isoniazid prophylaxis in the homeless: a randomized controlled trial.

OBJECTIVES: To test 2 interventions to improve adherence to isoniazid preventive therapy for tuberculosis in homeless adults. We compared (1) biweekly directly observed preventive therapy using a $5 monetary incentive and (2) biweekly directly observed preventive therapy using a peer health adviser, with (3) usual care at the tuberculosis clinic. METHODS: Randomized controlled trial in tuberculosis-infected homeless adults. Outcomes were completion of 6 months of isoniazid treatment and number of months of isoniazid dispensed. RESULTS: A total of 118 subjects were randomized to the 3 arms of the study. Completion in the monetary incentive arm was significantly better than in the peer health adviser arm (P = .01) and the usual care arm (P = .04), by log-rank test. Overall, 19 subjects (44%) in the monetary incentive arm completed preventive therapy compared with 7 (19%) in the peer health adviser arm (P = .02) and 10 (26%) in the usual care arm (P = .11). The median number of months of isoniazid dispensed was 5 in the monetary incentive arm vs 2 months in the peer health adviser arm (P = .005) and 2 months in the usual care arm (P = .04). In multivariate analysis, independent predictors of completion were being in the monetary incentive arm (odds ratio, 2.57; 95% CI, 1.11-5.94) and residence in a hotel or other stable housing at entry into the study vs residence on the street or in a shelter at entry (odds ratio, 2.33; 95% CI, 1.00-5.47). CONCLUSIONS: A $5 biweekly cash incentive improved adherence to tuberculosis preventive therapy compared with a peer intervention or usual care. Living in a hotel or apartment at the start of treatment also predicted the completion of therapy.

HIV-1 genotypic resistance patterns predict response to saquinavir-ritonavir therapy in patients in whom previous protease inhibitor therapy had failed.

BACKGROUND: Tests for resistance to HIV drugs are available for clinical use; however, their predictive value has not been fully assessed. OBJECTIVES: To determine HIV-1 genotypic predictors of a virologic response to saquinavir-ritonavir therapy in patients in whom at least one previous protease inhibitor-containing regimen had failed and to compare the predictive value of baseline genotype with that of standard clinical evaluation. DESIGN: Retrospective clinical cohort study. SETTING: University-based HIV clinic. PATIENTS: 54 HIV-1-infected adults treated with saquinavir-ritonavir who had experienced virologic failure while receiving a protease inhibitor-containing regimen for at least 3 months. MEASUREMENTS: HIV-1 reverse transcriptase and protease gene sequences, CD4 cell counts, clinical characteristics, detailed antiretroviral treatment history, and plasma HIV-1 RNA levels at baseline and at three follow-up time points (median, 4, 12, and 26 weeks). Virologic failure was defined as a plasma HIV RNA level greater than 1000 copies/mL. RESULTS: In 22 patients (41%), a plasma HIV-1 RNA level less than 500 copies/mL was achieved by week 12; in 15 patients (28%), this response was maintained through week 26. Clinical characteristics predicting a poorer response included a diagnosis of AIDS, lower CD4 cell count, and higher plasma HIV RNA level (P<0.03). Number of previous nucleoside reverse transcriptase inhibitors, previous protease inhibitor therapy, and duration of previous protease inhibitor therapy were predictors of poorer response (P<0.01). Multivariate regression models revealed that protease mutations present at the initiation of saquinavir-ritonavir therapy were the strongest predictors of virologic response. A model of clinical features explained up to 45% of the variation in virologic outcomes by week 12, whereas the explained variance was 71% when genotypic predictors were included. CONCLUSIONS: In patients in whom protease inhibitor-containing antiretroviral therapy fails, HIV-1 genotype is predictive of virologic response to subsequent therapy. This predictive capacity adds to that of standard clinical evaluation.

Clinical resistance patterns and responses to two sequential protease inhibitor regimens in saquinavir and reverse transcriptase inhibitor-experienced persons.

The efficacy of sequential protease inhibitor therapy was studied in 16 human immunodeficiency virus (HIV) 1-infected persons in whom saquinavir with multiple nucleoside reverse transcriptase (RT) inhibitors (NRTI) had failed. Nelfinavir plus two NRTIs (new or continued) resulted in minimal (0.59 log RNA copies/mL) and transient (8 weeks) suppression of plasma HIV RNA levels. Rapid failure was surprisingly associated with baseline presence of protease gene mutation L90M (P=.04) in the absence of D30N and with RT mutations D67N (P<.01), K70R/S (P=.02), and K219Q/W/R/E (P<.01). Ten patients were subsequently switched to indinavir plus nevirapine and 2 NRTIs, resulting in a median 1.62 log reduction in plasma HIV RNA, with 3 patients maintaining 400 copies/mL for 24 weeks. These results suggest that nelfinavir may have limited utility after saquinavir failure, particularly without potent concomitant therapy. Combining an NRTI with a new protease inhibitor for rescue may improve response.

Association between time homeless and perceived health status among the homeless in San Francisco.

The purpose of this study was to describe the perceived health of the homeless, and to measure the effect of time homeless on perceived health status, after controlling for sociodemographic characteristics and health conditions. The design was cross-sectional; the population was a representative sample of homeless in San Francisco, interviewed on health issues. Analysis of predictors of poor or fair health status was by logistic regression. In this sample of 2780 persons, 37.4% reported that their health status was poor or fair as compared to good or excellent. Reporting poor or fair health status was significantly associated with time homeless, after controlling for sociodemographic variables and health problems including results from screening for HIV and TB (OR = 1.49, 95% CI 1.24-1.79). Comparisons with data from the National Health Interview Survey (NHIS) showed poorer health status among the homeless persons in this study. Standardized morbidity ratios were highest for asthma; there was twice the number of homeless persons reporting asthma, in younger as well as older adults, as would be expected using NHIS rates. There was also an excess of arthritis, high blood pressure and diabetes in those age 18-44 as compared to adults in the Health Interview Survey. The time spent homeless remains associated with self-reported health status, after known contributors to poor health are controlled. Persons who have been homeless for longer periods of time may be the persons to whom health care interventions should be aimed.

Tuberculosis prophylaxis in the homeless. A trial to improve adherence to referral.

BACKGROUND: Adherence to tuberculosis evaluation is poor in a high-risk population such as the homeless. OBJECTIVE: To test two interventions aimed at improving adherence to tuberculosis evaluation and to identify predictors of adherence. METHODS: We conducted a randomized clinical trial in shelters and food lines in the inner city of San Francisco, Calif. We randomized 244 eligible subjects infected with tuberculosis to (1) peer health adviser (assistance by a peer [n = 83]), (2) monetary incentive ($5 payment [n = 82]), or (3) usual care (referral slips and bus tokens only [n = 79]). The primary outcome of the study was adherence to a first follow-up appointment at the tuberculosis clinic, where subjects were evaluated for active tuberculosis and the need for isoniazid prophylaxis. RESULTS: Of the subjects assigned to a monetary incentive, 69 (84%) completed their first follow-up appointment, compared with 62 subjects (75%) assigned to a peer health adviser and 42 subjects (53%) assigned to usual care. Adherence was higher in the monetary incentive and peer health adviser groups than in the usual care group (P < .001 and P = .004, respectively). Patients not using intravenous drugs and patients 50 years of age or older were more likely to adhere to a first follow-up appointment (odds ratios [95% confidence intervals], 2.5 [1.3 to 5.0] and 3.3 [1.2 to 8.8], respectively). Among the 173 tuberculosis-infected subjects who completed their appointment, isoniazid therapy was started for 72 individuals, and three cases of active tuberculosis were identified. CONCLUSION: A monetary incentive or a peer health adviser is effective in improving adherence to a first follow-up appointment in homeless individuals infected with tuberculosis. A monetary incentive appears to be superior. Intravenous drug users and young individuals are at high risk for poor adherence to referral.

Evidence for genetic regulation of susceptibility to toxoplasmic encephalitis in AIDS patients.

The frequency of HLA-DQ antigens in AIDS patients with toxoplasmic encephalitis (TE) were examined. HLA-DQ3 was significantly more frequent in white North American AIDS patients with TE (85.0%) than in the general white population (51.8%; P = .007, corrected P = .028) or randomly selected control AIDS patients who had not developed TE (40.0%; P = .016). In contrast, the frequency of HLA-DQ1 was lower in TE patients than in healthy controls (40.0% vs. 66.5%, P = .027), but this difference did not reach statistical significance when corrected for the number of variables tested (corrected P = .108 for the general white population). HLA-DQ3 thus appears to be a genetic marker of susceptibility to development of TE in AIDS patients, and DQ1 may be a resistance marker. These HLA associations with disease indicate that development of TE in AIDS patients is affected by a gene or genes in the HLA complex and that HLA-DQ typing may help in decisions regarding TE prophylaxis.

HIV and tuberculosis infection in San Francisco's homeless adults. Prevalence and risk factors in a representative sample.

OBJECTIVE: To determine the prevalence and risk factors for human immunodeficiency virus (HIV) and tuberculosis (TB) infection and investigate the relationship between these two infections in homeless adults. DESIGN: Cross-sectional study. SETTING: Inner-city shelters and free meal programs. PARTICIPANTS: A representative sample of 1226 adults (> or = 18 years) were enrolled from community sites. MAIN OUTCOME MEASURES: Serum HIV-1 antibody status and tuberculin skin test reactivity. RESULTS: Human immunodeficiency virus seroprevalence was 8.5% (95% confidence interval [CI], 7.0% to 10.1%) and the prevalence of TB infection was 32% (95% CI, 30% to 37%). Nineteen percent of the HIV-seropositive subjects had positive tuberculin skin tests. Independent risk factors for HIV infection included younger age, black race, male homosexual contact, injection drug use, use of injection drugs in shooting galleries, and selling sex. Tuberculosis infection was associated with the duration of homelessness and living in crowded shelters or single-room-occupancy hotels. Injection drug use, a risk factor for HIV, was also a risk factor for TB, with a particularly strong association in women. No evidence of an association between TB and HIV infection was found, even after accounting for anergy. CONCLUSIONS: The homeless population in the United States should be considered a group at high risk for HIV infection and TB. Given the constellation of risk factors present, the high prevalence of infection, and lack of access to medical services, we anticipate that these communicable diseases in this population will represent a growing public health problem.