Anti-BLyS Treatment of 36 Israeli Systemic Lupus Erythematosus Patients.

BACKGROUND: Anti-BLyS treatment with the human belimumab monoclonal antibody was shown to be a safe and effective therapeutic modality in lupus patients with active disease (i.e., without significant neurological/renal involvement) despite standard treatment. OBJECTIVES: To evaluate the "real-life" safety and efficacy of belimumab added to standard therapy in patents with active lupus in five Israeli medical centers. METHODS: We conducted a retrospective open-labeled study of 36 lupus patients who received belimumab monthly for at least 1 year in addition to standard treatment. Laboratory tests (C3/C4, anti dsDNA autoantibodies, chemistry, urinalysis and complete blood count) were done every 3-4 months. Adverse events were obtained from patients' medical records. Efficacy assessment by the treating physicians was defined as excellent, good/partial, or no response. RESULTS: The study group comprised 36 lupus patients (8 males, 28 females) with a mean age of 41.6 } 12.2 years. Belimumab was given for a mean period of 2.3 } 1.7 years (range 1-7). None of the patients discontinued belimumab due to adverse events. Four patients (11.1%) had an infection related to belimumab. Only 5 patients (13.9%) stopped taking belimumab due to lack of efficacy. The response was excellent in 25 patients (69.5%) and good/partial in the other 6 (16.6%). Concomitantly, serological response (reduction of C3/C4 and anti-dsDNA autoantibodies) was also observed. Moreover, following belimumab treatment, there was a significant reduction in the usage of corticosteroids (from 100% to 27.7%) and immunosuppressive agents (from 83.3% to 8.3%). CONCLUSIONS: Belimumab, in addition to standard therapy, is a safe and effective treatment for active lupus patients.

Strongyloidiasis-Related IRIS.

Helminthic infection and HIV have been reported to coexist, particularly in sub-Saharan African patients living with HIV. Strongyloidiasis is one of the most common helminths, usually leading to cutaneous and gastrointestinal (GI) symptoms. In the immunocompromised host, this infection can lead to strongyloidiasis hyperinfection syndrome (SHS), not common in HIV-infected patients. Immune reconstitution inflammatory syndrome (IRIS) can follow the initiation of antiretroviral therapy (ART), with a variety of presentations. The authors present here a 32-year-old HIV-infected female who was recently diagnosed with AIDS, started ART, and recovered from SHS. Her upper endoscopy revealed severe duodenitis but no causal agent per biopsy or stool examination. After receiving symptomatic therapy, she showed improvement, a course of events that fit the diagnosis of GI-related IRIS.

A Population-Structured HIV Epidemic in Israel: Roles of Risk and Ethnicity.

BACKGROUND: HIV in Israel started with a subtype-B epidemic among men who have sex with men, followed in the 1980s and 1990s by introductions of subtype C from Ethiopia (predominantly acquired by heterosexual transmission) and subtype A from the former Soviet Union (FSU, most often acquired by intravenous drug use). The epidemic matured over the last 15 years without additional large influx of exogenous infections. Between 2005 and 2013 the number of infected men who have sex with men (MSM) increased 2.9-fold, compared to 1.6-fold and 1.3-fold for intravenous drug users (IVDU) and Ethiopian-origin residents. Understanding contemporary spread is essential for effective public health planning. METHODS: We analyzed demographic and virologic data from 1,427 HIV-infected individuals diagnosed with HIV-I during 1998-2012. HIV phylogenies were reconstructed with maximum-likelihood and Bayesian methods. RESULTS: Subtype-B viruses, but not A or C, demonstrated a striking number of large clusters with common ancestors having posterior probability ≥0.95, including some suggesting presence of transmission networks. Transmitted drug resistance was highest in subtype B (13%). MSM represented a frequent risk factor in cross-ethnic transmission, demonstrated by the presence of Israeli-born with non-B virus infections and FSU immigrants with non-A subtypes. CONCLUSIONS: Reconstructed phylogenetic trees demonstrated substantial grouping in subtype B, but not in non-MSM subtype-A or in subtype-C, reflecting differences in transmission dynamics linked to HIV transmission categories. Cross-ethnic spread occurred through multiple independent introductions, with MSM playing a prevalent role in the transmission of the virus. Such data provide a baseline to track epidemic trends and will be useful in informing and quantifying efforts to reduce HIV transmission.

Evaluation of GS Junior and MiSeq next-generation sequencing technologies as an alternative to Trugene population sequencing in the clinical HIV laboratory.

Population HIV-1 sequencing is currently the method of choice for the identification and follow-up of HIV-1 antiretroviral drug resistance. It has limited sensitivity and results in a consensus sequence showing the most prevalent nucleotide per position. Moreover concomitant sequencing and interpretation of the results for several samples together is laborious and time consuming. In this study, the practical use of GS Junior and MiSeq bench-top next generation sequencing (NGS) platforms as an alternative to Trugene Sanger-based population sequencing in the clinical HIV laboratory was assessed. DeepChek(®)-HIV TherapyEdge software was used for processing all the protease and reverse transcriptase sequences and for resistance interpretation. Plasma samples from nine HIV-1 carriers, representing the major HIV-1 subtypes in Israel, were compared. The total number of amino acid substitutions identified in the nine samples by GS Junior (232 substitutions) and MiSeq (243 substitutions) was similar and higher than Trugene (181 substitutions), emphasizing the advantage of deep sequencing on population sequencing. More than 80% of the identified substitutions were identical between the GS Junior and MiSeq platforms, most of which (184 of 199) at similar frequency. Low abundance substitutions accounted for 20.9% of the MiSeq and 21.9% of the GS Junior output, the majority of which were not detected by Trugene. More drug resistance mutations were identified by both the NGS platforms, primarily, but not only, at low abundance. In conclusion, in combination with DeepChek, both GS Junior and MiSeq were found to be more sensitive than Trugene and adequate for HIV-1 resistance analysis in the clinical HIV laboratory.

Assessment of the knowledge and attitudes regarding HIV/AIDS among pre-clinical medical students in Israel.

BACKGROUND: Today's medical students are the future physicians of people living with HIV/AIDS (PLWHA). It is therefore essential that medical students possess the appropriate knowledge and attitudes regarding PLWHA. This study aims to evaluate knowledge and attitudes of pre-clinical Israeli medical students and to assess whether their knowledge and attitudes change throughout their pre-clinical studies. METHODS: A cross-sectional study was conducted among all pre-clinical medical students from the four medical schools in Israel during the academic year of 2010/2011 (a total of 1,470 students). A self-administered questionnaire was distributed. The questionnaire sought student responses pertaining to knowledge of HIV transmission and non-transmission routes, basic knowledge of HIV/AIDS treatment and attitudes towards HIV/AIDS. RESULTS: The study's response rate was 62.24 percent. Knowledge among pre-clinical medical students was generally high and showed a statistically significant improvement as students progressed through their pre-clinical studies. However, there were some misconceptions, mostly regarding HIV transmission via breastfeeding and knowledge of HIV prevention after exposure to the virus. Students' attitudes were found to include stigmatizing notions. Furthermore, the majority of medical students correlated HIV with shame and fear. In addition, students' attitudes toward HIV testing and providing confidential medical information were contradictory to health laws, protocols and guidelines. Overall, no positive changes in students' attitudes were observed during the pre-clinical years of medical school. CONCLUSION: The knowledge of pre-clinical medical students in Israel is generally high, although there are some knowledge inadequacies that require more emphasis in the curricula of the medical schools. Contrary to HIV-related knowledge, medical students' attitudes are unaffected by their progression through medical school. Therefore, medical schools in Israel should modify their curricula to include teaching methods aimed at improving HIV-related attitudes and adherence to medical professionalism.

[Fertility treatment options for discordant couples living with HIV].

BACKGROUND: Serodiscordant couples live with the risk of HIV infection of the negative partner when attempting to become pregnant. Using density gradient centrifugation (DGC), spermatozoa can be separated from other seminal compartments. Isolated spermatozoa do not contain detectable HIV RNA. DGC followed by artificial insemination may significantly reduce the risk of infection. The Hadassah AIDS Center (HAC) has recently initiated a fertility center for serodiscordant couples. METHODS: Our patient population includes serodiscordant couples in which the male is HIV positive. The male semen is washed using the DGC procedure. Washed semen is tested for HIV by standard PCR methods. Intrauterine insemination (IUI) is attempted using the washed semen. RESULTS: A total of 55 couples have registered for this procedure. This includes 16 men who have sex with men, 7 who have hemophilia and 8 couples of Ethiopian origin. The average female age is 33 years. Seven (12%) men had inadequate sperm counts and were referred for IVF. Overall, 34 semen samples were tested for HIV. Only one was found to be positive. During the procedure, 22 couples underwent at least one IUI attempt and 16 (72%) females became pregnant, 3 of them after the first IUI attempt. All women tested for HIV after IUI were found to be negative. CONCLUSIONS: The pregnancy success rate during the first year of operation was 72%, similar to that reported by other centers in Europe. There were no seroconversions of the female partner. Serodiscordant couples living with HIV in Israel today may consider starting a family, while significantly reducing the risk of infecting the negative female partner.

Hypersensitivity and desensitization to darunavir in a case of HIV infection with triple-class drug resistance: case description and review of the literature.

We report on a case of severe cutaneous reaction to darunavir/r and a successful desensitization protocol. The patient was a 41-yr old female. known to be HIV infective for 18 years and who had received several drug regiments in the past. As a consequence, her virus had triple-class mutations but was susceptible to darunavir/r. Her CD4 was 200 cells/mm(3) and HIV viral load 56,000 copies/mL. Eight days after initiation of darunavir/r the patient developed a severe pruritic vesicular extended cutaneous allergic reaction which required cessation of all drugs. Due to the severity of the allergic reaction no rechallenge was done. After the patient's recovery, the virus was found to be susceptible only to maraviroc, raltegravir, and darunavir/r. Since darunavir/r was an essential component in treating this triple-class mutated virus, a desensitization protocol was applied successfully. Six months after desensitization protocol was applied successfully. Six months after desensitization, the patient is asymptomatic, compliant, and her HIV viral load remains at <20 copies/mL.

A case of possible darunavir/ritonavir-induced peripheral neuropathy: case description and review of the literature.

A 65-year-old man, M.S.M., known as being HIV infected for 20 years, presented with muscle ache and progressive weakness 3 months after initiation of darunavir as a part of his antiretroviral therapy (ART). The patient's treatment included darunavir/ritonavir 600/100 mg twice daily, plus a backbone of didanosine and abacavir which were the backbone in his previous regimen for several years according to his drug resistance profile. Three months after initiation of darunavir/ritonavir the patient exhibited clinical symptoms of severe pain and progressive weakness of his lower limbs; he was unable to walk and was totally wheelchair-bound. Severe sensory peripheral polyneuropathy was revealed on electromyogram (EMG). All medications, including ART, were stopped. Within two months, concomitantly with initiation of raltegravir, etravirine and emcitricabine/tenofovir, the patient recovered, gained weight, resumed walking and his CD4 counts rose from 270 to 450 cells/mm(3). A second EMG study 3 months after initiation of his new ART regimen showed compete recovery of the previously diagnosed peripheral neuropathy. In this report, we present a case of severe HIV-1-related acute demyelinating polyneuropathy which initiated after new generation PI darunavir/ritonavir was given and resolved after cessation of the drug without the use of immune-based therapies. The variety of HIV-related polyneuropathies will be discussed.

[Outcome of treatment with peg-interferon and ribavirin in HIV-HCV co-infected patients: "real life" single center experience].

BACKGROUND AND AIM: Recently, with the emergence of highly effective antiretroviral treatment (ART), chronic liver disease has become the leading cause of morbidity and mortality in co-infected HIV-HCV (Human immunodeficiency virus-Hepatitis C virus) patients. The overall SVR rate in this population remains unsatisfactory. The aim of this study was to evaluate the response to therapy in HIV-HCV co-infected patients in a single center. PATIENTS AND METHODS: Consecutive HIV-HCV co-infected patients were evaluated in the liver clinic between 2003 -2010. Liver needle biopsy was conducted in 100% of the patients. The patients were treated by a multidisciplinary team consisting of immunologists, hepatologists, social workers and nurses and a close follow-up was conducted. The 48 weeks duration of peg-interferon and ribavirin combination was used for all genotypes according to recent guidelines. Weight-adjusted ribavirin doses were applied. Treatment was initiated after stabilization of HIV parameters and successful weaning from drug and alcohol addiction. RESULTS: A total of 86 out of 143 HIV- HCV co-infected patients, were evaluated; 39 completed treatment. Of those 31 (77%) achieved SVR. Out of 22 genotype 1 patients, 18 (82%) achieved SVR. Six patients had spontaneous viral clearance and 8 are still receiving treatment. In 17 non-one genotype patients, the SVR rate was 76.4% (13 of 17 patients); 6 patients were defined as relapsers and non-responders. Overall adherence to the treatment was high. CONCLUSION: Measures, such as the use of a multidisciplinary approach, high adherence of physicians to the guidelines, weight-based ribavirin dose, and selecting patients who are ready to start therapy, can significantly improve the SVR rate in this difficult-to-treat patient population.

Psychological distress, life stressors, and social support in new immigrants with HIV.

The expression of psychological distress is culture-dependent. Ethiopian Jewish immigrants' expression of distress is anchored in their unique culture. The authors' aim in this study was to assess the psychological distress of HIV-positive (HIV+) Ethiopian Jewish immigrants in Israel, using a culture-based tool, and to examine the relations of psychological distress, psychosocial variables, and T lymphocyte subset counts and viral load. Participants were 56 HIV+ patients. The authors assessed psychological distress by the self-report questionnaire, which they adjusted for the Ethiopian immigrants (SRQ-E). The authors also assessed adherence to treatment regimen, number of life stressors, and degree of perceived social support, T lymphocyte subset counts, and viral load in plasma. The overall level of psychological distress was in the high range of the SRQ-E scale and was considerably higher in men than in women. Psychological distress was related to more life stressors and lower perceived social support. Women reported having more social support, had better T(CD4+) lymphocyte count and T(CD4+)/T(CD8+) ratio, and lower viral load than did men. Better HIV indicators were related to shorter duration of HIV+ since diagnosis, better adherence, and more social support, but not to psychological distress. The culture-based tool allowed identification of the high degree of psychological distress among the HIV+ Ethiopian immigrants. Researchers need to assess the adaptability of culture-based questionnaires to determine psychological distress in HIV+ patients.

Comparative performance of the Amplicor HIV-1 Monitor Assay versus NucliSens EasyQ in HIV subtype C-infected patients.

In facing global programs for treating HIV-infected patients in the developing countries, there is a real need for viral load assays that are accurate for the local subtypes. The present study was designed to evaluate viral load measurements using the newer version of the NASBA assay in subtype C-infected patients. The performances of this new version, a real-time nucleic acid sequence-based amplification HIV-1 assay (NucliSens EasyQ), were compared to Amplicor HIV-1 Monitor Assay version 1.5 in 79 samples of subtype C-infected patients originating from Ethiopia. Twenty HIV-1 subtype B-infected patients served as a control group. Blood samples from patients in both groups were tested by both assays. The results were compared by a paired, two-tailed Student's t-test. The disparity between the results of the two viral load assays was highly significant in subtype C samples (P = 0.005), such that in the vast majority, higher values of viral load were obtained by the Amplicor assay. However, no differences between the two assays were found in subtype B samples (P = 0.77). CD4 measurements were available for 78 samples of subtype C-infected patients. Of these, a CD4-to-viral load discrepancy (CD4

Absence of HIV-associated nephropathy in Ethiopians.

BACKGROUND: Population-based epidemiological surveys in several countries have shown approximately 10- to 15-fold increased susceptibility to human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) for populations of recent African ancestry. Accordingly, we sought to determine whether a similar or different pattern of susceptibility was evident among Ethiopians followed up in an HIV clinic in Israel. METHODS: One hundred seventy-six consecutive patients (126 Ethiopians, 50 non-Ethiopian Israelis) followed up at the HIV clinic of Rambam Medical Center in northern Israel were examined for the presence of proteinuria and/or decreased glomerular filtration rate. HIV viral load, CD4 count, and treatment modality also were determined. RESULTS: Overall, 73% of patients were treated with highly active antiretroviral therapy, and there was no difference between Ethiopians and non-Ethiopian Israelis in this regard. Mean CD4 count in Ethiopians was 288 +/- 140/microL, significantly less than the corresponding CD4 count of 398 +/- 190/microL for non-Ethiopian Israelis. Mean viral loads were greater in Ethiopians compared with non-Ethiopian Israelis. None of 176 HIV-infected patients fulfilled clinical criteria for HIVAN as delineated in this study. CONCLUSION: HIV-infected individuals of Ethiopian descent have a level of susceptibility to HIVAN similar to that of non-Ethiopian Israelis, which is strikingly less than that reported for other populations for recent African ancestry. This does not appear to be attributable to differences in HIV infection control or viral subtype and most likely represents population-based differences in host genetic factors. This finding emphasizes the importance of avoiding generalizations with respect to phylogeographic ancestry in disease-susceptibility studies.

The association of thrombocytopenia with systemic manifestations in the antiphospholipid syndrome.

Thrombocytopenia is frequently found in patients with the antiphospholipid syndrome (APS), yet data concerning clinical associations of thrombocytopenia in patients with APS are still scarce. We evaluated possible associations between thrombocytopenia and various APS-related manifestations in a large group of APS patients. Three hundred and seven APS patients were retrospectively evaluated, 259 women and 48 men. Most patients had primary APS (PAPS) (n=173, 56.1%). APS was associated with systemic lupus erythematosus (SLE) in 104 patients (33.9%). All patients underwent detailed medical interview and routine physical examination. Further data were obtained from patients' medical files regarding the expression of various clinical manifestations of the disease. There were 90 patients with thrombocytopenia (29.3%), the rate was significantly higher in SLE compared to PAPS patients (41.9% vs. 23.1%, p=0.001). Similar rates of thrombocytopenia were found in male (29.2%) and female (29.3%) patients. Significant associations were found between thrombocytopenia and cardiac valves thickening and dysfunction, epilepsy, chorea, arthritis, livedo reticularis and skin ulcerations. In contrast, the rates of thrombotic episodes as well as obstetric complications were similar in patients with and without thrombocytopenia. Our data suggest the presence of thrombocytopenia may be a risk factor for cardiac, neurological, articular and cutaneous complications in APS.

[Insemination from HIV-positive males].

INTRODUCTION: Discordant couples, in which the man is HIV positive and the woman is HIV negative, face limited options when they wish to produce healthy children whilst practicing safe sex. In order to conceive they must abandon unprotected sex, which carries high risk of HIV infection to the woman. OBJECTIVE: To develop a method for removing the HIV from semen and then perform intra uterine insemination, following verification of the HIV-negative spermatozoa fraction by PCR. METHODS: Motile spermatozoa were isolated from semen samples by the gradient and "swim-up" techniques. HIV-RNA was tested before and after the procedure in both the semen and the purified spermatozoa fraction. Insemination was performed on ovulation day only when the absence of any viral particles was verified by PCR. RESULTS: Four couples underwent a total of 8 cycles of intra uterine insemination (IUI). Presently, two healthy babies were born. The two mothers and newborn were found to be HIV negative following the delivery. CONCLUSION: We report a safe procedure which enables biological parenthood for HIV-1 discordant couples without the risk of infecting the female partner. Our clinical data corroborate with the collaborative European data on this subject.

Features associated with epilepsy in the antiphospholipid syndrome.

OBJECTIVE: To assess the frequency of epilepsy in primary and secondary antiphospholipid syndrome (APS); to analyze the clinical and laboratory features characterizing those with epilepsy in a cohort of 538 patients with APS; and to find associated features that would suggest risk factors for epilepsy in APS. METHODS: We analyzed the clinical features of patients with APS who had epilepsy and compared them to the clinical features of non-epileptic APS patients. RESULTS: Of 538 APS patients, 46 (8.6%) had epilepsy. Epilepsy was more prevalent among APS secondary to systemic lupus erythematosus (SLE) compared to primary APS (13.7% vs 6%; p < 0.05). The patients with epilepsy had a higher prevalence of central nervous system (CNS) manifestations including focal ischemic events (strokes or transient ischemic events, 54.3% vs 24.6%; p < 0.0001) and amaurosis fugax (15.2% vs 4.9%; p < 0.05). APS patients with epilepsy had a higher frequency of valvular pathology (30.4% vs 14.6%; p < 0.01), thrombocytopenia (43.5% vs 25%; p < 0.05), and livedo reticularis (26.1% vs 11.5%; p < 0.01). The multivariate logistic regression analysis found CNS thromboembolic events as the most significant factor associated with epilepsy, with an odds ratio (OR) of 4.05 (95% confidence interval, CI: 2.05-8), followed by SLE (OR 1.4, 95% CI 1.2-4.7), and valvular vegetations (OR 2.87, 95% CI 1-8.27). CONCLUSION: Epilepsy is common in APS and most of the risk seems to be linked to vascular disease as manifested by extensive CNS involvement, valvulopathy, and livedo reticularis and to the presence of SLE. These factors, however, explain only part of the increased occurrence of epilepsy in APS and other causes such as direct immune interaction in the brain should be investigated.

Mutation D30N is not preferentially selected by human immunodeficiency virus type 1 subtype C in the development of resistance to nelfinavir.

Differences in baseline polymorphisms between subtypes may result in development of diverse mutational pathways during antiretroviral treatment. We compared drug resistance in patients with human immunodeficiency virus subtype C (referred to herein as "subtype-C-infected patients") versus subtype-B-infected patients following protease inhibitor (PI) therapy. Genotype, phenotype, and replication capacity (Phenosense; Virologic) were determined. We evaluated 159 subtype-C- and 65 subtype-B-infected patients failing first PI treatment. Following nelfinavir treatment, the unique nelfinavir mutation D30N was substantially less frequent in C (7%) than in B (23%; P = 0.03) while L90M was similar (P < 0.5). Significant differences were found in the rates of M36I (98 and 36%), L63P (35 and 59%), A71V (3 and 32%), V77I (0 and 36%), and I93L (91 and 32%) (0.0001 < P < 0.05) in C and B, respectively. Other mutations were L10I/V, K20R, M46I, V82A/I, I84V, N88D, and N88S. Subtype C samples with mutation D30N showed a 50% inhibitory concentration (IC(50)) change in susceptibility to nelfinavir only. Other mutations increased IC(50) correlates to all PIs. Following accumulation of mutations, replication capacity of the C virus was reduced from 43% +/- 22% to 22% +/- 15% (P = 0.04). We confirmed the selective nature of the D30N mutation in C, and the broader cross-resistance of other common protease inhibitor mutations. The rates at which these mutational pathways develop differ in C and subtype-B-infected patients failing therapy, possibly due to the differential impact of baseline polymorphisms. Because mutation D30N is not preferentially selected in nelfinavir-treated subtype-C-infected patients, as it is in those infected with subtype B, the consideration of using this drug initially to preserve future protease inhibitor options is less relevant for subtype-C-infected patients.

Measurement of HIV RNA in patients infected by subtype C by assays optimized for subtype B results in an underestimation of the viral load.

Quantitation assays of HIV-1 RNA used currently were designed and optimized for subtype B viruses. However, infection with non-B HIV viruses has become more common worldwide. Unfortunately, little information is available regarding the suitability of these assays for measurement of viral load in specific non-B subtypes. The performance of two commercial HIV-1 RNA quantitation assays was evaluated in 82 HIV subtype C-infected patients and in 43 HIV-1 subtype B-infected patients. Blood samples were tested by the Amplicor HIV-1 Monitor Assay, Version 1.5, and by the nucleic acid sequence-based amplification HIV-1 assay (NucliSens). The results were compared by using a paired, two-tailed Student's t-test; the difference between the assays was found to be significant only for subtype C. Discordant results (>0.5 log difference) between the two assays were detected in 39% of subtype C samples, compared to 23.2% of subtype B samples. In all cases in which a discordant result was detected, the lower results were obtained by the NucliSens assay. Discordant results between CD4 and viral load (CD4 < 200 cells/ml with a viral load <5,000 copies/ml) were observed in eight of the subtype C-infected patients when a viral load was measured by NucliSens (9.7%), compared to three patients (3.6%) when measured by the Amplicor assay. In conclusion, in patients with HIV subtype C infection, measurement of HIV RNA by the NucliSens assay resulted in a significant underestimation of the viral load as compared to the Amplicor assay. As a consequence, such an underestimation may result in sub-optimal care of patients infected with HIV subtype C.

Genetic variation at NNRTI resistance-associated positions in patients infected with HIV-1 subtype C.

OBJECTIVE: Genetic differences between subtypes of HIV-1, even when not associated with key resistance mutations, are known to affect baseline susceptibility to specific antiretroviral drugs and resistance-development pathways. We studied the prevalence and patterns of non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated mutations in HIV-1 subtype C-infected patients. METHOD: We analysed the genetic variation at sites associated with NNRTI and nucleoside reverse transcriptase inhibitor resistance in subtype C- versus B-infected patients, both drug-naive and -experienced. We extended the comparison to subtype B records from the Stanford database. RESULTS: A total of 150 subtype B and 341 subtype C-infected patients were studied. No significant differences were found in treatment and clinical parameters between the groups. In NNRTI-naive patients, changes in NNRTI positions were present in 9.3% of subtype B- versus 33.1% of subtype C-infected patients (P < 0.001). Differences were seen in both drug-naive (subtype B, 10.0% versus subtype C, 50.1%; P < 0.021) and drug-experienced NNRTI-naive patients (subtype B, 9.0% versus subtype C, 23.8%; P < 0.001). In NNRTI experienced patients, the number of A98G/S changes was significantly higher in subtype C patients treated with either efavirenz or nevirapine (P < 0.0001), and V106M was higher in efavirenz-treated subtype C-infected patients (P < 0.0001). The average mutation rates were 1.26 and 1.67 per patient for subtypes B and C, respectively (P = 0.036). The frequency of nucleoside associated mutations, but not M184V, in treated patients was significantly higher in subgroup B-infected patients (P = 0.028). CONCLUSION: Collectively, these data indicate that genetic variation at NNRTI resistance-associated positions such as V106M and A98S is substantially greater in subtype C-infected patients than in subtype B-infected patients. The natural structure of each subtype probably affects the frequency and pattern of drug resistance mutations selected under treatment.