Management of HIV

INITIAL EVALUATION OF AN HIV POSITIVE PATIENT

1. Complete medical history-

This should include the following

a) History regarding possible time and source of infection if possible. This is required to identify the transmission category.

b) History of previous HIV testing, the reason for same and the results.

c) History of HIV related symptoms- past and current.

d) History of opportunistic and other infections in the past.

e) History of possible contact with tuberculosis.

f) Sexual history and past history of STDs

g) Co morbidities- HT, IHD, DM, risk factors for IHD like smoking, obesity, dyslipidemia and family history of IHD. Pulmonary, renal,gastrointestinal, Skin, neurologic, hematologic, psychiatric illness and any surgeries in the past .

h) Depression screening

i) History of drug abuse , smoking and alcoholism

j) Drug history- current and previous antiretroviral treatment and prophylaxis for opportunistic infections.

k) History of oral contraceptive pill use and pregnancy history in women.

2. Patient examination-

A complete physical examination including

a) Nutritional assesment

b) Oropharynx- check for candidiasis, oral hairy leucoplakia

c) Lymphadenopathy – generalized or asymmetric

d) Skin- look for seborrheic dermatitis, psoriasis, folliculitis, Kaposi’s sarcoma, common warts, and molluscum contagiosum

e) Systemic examination

f) Fundoscopic examination( in patients with CD4+ count < 100cells/cumm for CMV retinitis)

g) Mini Mental Scale Examination

3. Laboratory tests-

a) CBC

b) CD4 counts : CD4 counts serve as a major clinical indicator of immunocompetence in HIV infected patients. A baseline CD4 count should be done followed by a followup count every 3 to 6 months in order to determine when to start HAART, to assess immunological response to HAART and to assess the need for initiating chemoprophylaxis for opportunistic infections.

c) Plasma HIV RNA levels : Should preferably done 6 months after starting antiretroviral therapy for evaluating the response to therapy.Plasma HIV RNA levels less than 400 copies /ml or 50 copies /ml indicate adequate viral suppression.

d) Complete biochemistry- RFT,LFT, BSF, lipid profile

e) Chest Xray

f) Serologic tests - VDRL
HBsAg, anti HCV
Optional tests- Anti HAV, anti Toxoplasma IgG, anti CMV IgG, anti Varicella IgG

g) PAP smear

h) Tuberculin test

TREATMENT OF HIV INFECTED PATIENT

HIV is currently not a curable disease but with advent of antiretroviral therapy it has become a chronic manageable disease. HAART (highly active retroviral therapy) and prophylaxis and treatment for opportunistic infections, is the cornerstone of management of patients with HIV infection. Patients should be educated and counselled regarding HIV infection, prevention of transmission, importance of regular monitoring and adherence to treatment once it is started. The WHO has published guidelines for antiretroviral therapy in resource limited areas.It aims to provide treatment to as many people as possible while working towards universal accesss to antiretroviral treatment.
The treatment goals of antiretroviral treatment are to reduce HIV related morbidity and mortality ,improve quality of life ,restore and preserve immunologic function and maximally and durably suppress viral load

WHEN TO START TREATMENT

Indications for initiating antiretroviral therapy for the chronically infected HIV-1 treatment naïve infected patient:

1. Treat patient with AIDS defining illness* or severe symptoms irrespective of CD4+ T cell count and plasma HIV RNA levels.(AI)

2. Treat asymptomatic patients with CD4+ T cell count less than 200/cumm irrespective of plasma HIV RNA levels.(AI)

3. Asymptomatic patients with CD4+T cell count more than 200 but less than or equal to 350 treatment should be offered treatment irrespective of Plasma HIV RNA levels after discussion with patients.(BII)

4. Asymptomatic patients with CD4+ T cell count more than 350 and plasma HIV RNA levels more than 100,000 most clinicians recommend deferring therapy but some clinicians will treat.(CII)

5. Asymptomatic patients with CD4+ T cell count more than 350 and plasma HIV RNA levels less than 100,000(DII),defer therapy.

*AIDS defining illness as per CDC Classification 1993. Severe symptoms include unexplained fever or diarrhea >2-4 weeks, oral candidiasis, or >10% unexplained weight loss.

Adapted from -Guidelines for the use of antiretroviral agents in HIV-1 Infected adults and Adolescents, DHHS Guidelines 2005

Factors To Consider When Selecting an Initial Regimen:

Comorbidity, adherence potential, dosing convenience, potential adverse drug effects,potential drug interaction, CD4+ T cell count, gender and pregnancy potential.

WHAT ARE THE PREFERRED REGIMENS

Three different types of combination regimens are as follows:

NNRTI based (1NNRTI+ 2 NRTIs), PI based (1-2 PI+2NRTIs) and triple NRTI based regimens.

Preferred regimen Alternative regimen

*EFV should not be given in women in first trimester of pregnancy or in those with high pregnancy potential.

Source -Guidelines for the use of antiretroviral agents in HIV-1 Infected adults and Adolescents, DHHS Guidelines 2005

Recommended NNRTI –based regimens for India:

Preferred – (ZDV or TDF)+ 3TC + (EFV or NVP)
Alternative – (d4T+3TC or ABC +3TC or ddI +3TC) +(NVP or EFV)
Source – API-ART Guidelines 2006

It is important to recognize any potential toxicity that might occur when using cancer chemotherapy with HAART. Research indicates that in most cases, combining the therapies is safe. However, some interactions are possible; for example, zidovudine should be avoided in patients receiving chemotherapy for cancer since both cause bone marrow toxicity. Also, some protease inhibitors may produce toxicity when combined with infusional cancer chemotherapy regimens.
In India, as per the National Aids Control Organisation the following first line regimens are used –

First line regimen – d4T+3TC+NVP

Alternate first line regimen – ZDV+3TC+NVP or

– d4T+3TC+ EFV

PRIMARY PROPHYLAXIS FOR OPPORTUNISTIC INFECTIONS

CD4+ Prophylaxis to be started against Level of recommendation

counts

All Hepatitis B Virus Generally recommended

Hepatitis A virus

Varicella zoster virus Strongly recommended

> 200 Streptococcus Pneumoniae Generally recommended

< 200 Pneumocystis carinii Strongly recommended

< 100 Toxoplasma gondii Strongly recommended

< 50 Mycobacterium avium complex Strongly recommended

Cryptococcus neoformans Evidence for efficacy but

not routinely indicated

Cytomegalovirus Evidence for efficacy but

(CMV antibody positivity) not for routinely indicated

Pneumocystis carinii

Indication: CD4+ count <200 or oropharyngeal candidiasis, CD4+ count >200 but < 250, CD4+ percentage of < 14% and for patients with history of an AIDS defining illness.

First   choice:   Trimethoprim _ sulfamethoxazole (TMP-SMZ), 1DS po q.d (AI)

Patients receiving treatment for toxoplasmosis with sulfadiazine and pyrimethamine are protected against pneumocystis carinii pneumonia and do not need additional prophylaxis against pneumocystis carinii

Mycobacterium Tuberculosis

INH prophylaxis is not recommended in India as the burden of TB is high and chemoprophylaxis may not prevent reinfection and wide spread use of INH may contribute to an increase in INH resistance.

Toxoplasma gondii

Indications:    Ig    G antibody to Toxoplasma and CD4+ count <100/cumm

First choice: TMP-SMZ, 1DS po q.d. (AII)

Mycobacterium avium complex

Indication: CD4+ count < 50/cumm

First choice: Azithromycin, 1,200 mg po q.w., (AI) or clarithromycin, 500 mg po b.i.d (AI)

Varicella zoster virus (VZV)

Indication: Significant exposure to chickenpox or shingles for patients who have no history of either condition or if available, negative antibody toVZV

First choice: Varicella zoster immune globulin (VZIG), 5 vials (1.25 ml each) IM, administered <=96 hours after exposure, ideally within 48 ho (AIII)

Streptococcus pneumoniae

Indication: CD4 count >= 200/cumm

First choice: 23valent polysaccharide vaccine, 0.5 ml IM

Hepatitis B virus

Indication: All susceptible (anti HBcnegative) patients

First choice: Hepatitis B vaccine 3 doses (BII)

Influenza virus

Indication: All patients annually before influenza season

First choice: Inactivated trivalent influenza virus vaccine : one annual dose (0.5 ml) im (BIII)

Hepatitis A virus

Indication: All susceptible (anti-hav negative) patients at increased risk for HAV infection (eg. Illicit drug users, men who have sex with men, hemophiliacs) or with chronic liver disease, including chronic hepatitis B or hepatitis C

First choice: Hepatitis a vaccine two doses (BIII)

Cryptococcus neoformans

Indication: CD4+ counts < 50/cummFirst choice: Fluconazole 100-200 mg po q.d.

Cytomegalovirus (CMV)

Indication: CD4+ count < 100/cumm, endemic geographic area

First choice: Oral Ganciclovir 1gm po tid. (CI)

POST EXPOSURE ANTI- RETROVIRAL PROPHYLAXIS

1. Assesment of exposure type and infection status of source should be done and PEP recommended accordingly

Recommended HIV PEP for percutaneous injuries

Infection status of source**

Exposure HIV positive HIV positive HIV Negative

type§ Class 1* Class2*

Less severe Recommend Recommend No PEP

basic 2 drug expanded 3 drug warranted

PEP PEP

More severe Recommend Recommend No PEP

expanded 3 expanded warranted

drug PEP 3 drug PEP

Recommended HIV PEP for skin exposures and non intact skin exposures

Infection status of source**

Exposure HIV positive HIV positive HIV Negative

type¶ Class 1* Class2*

Small Consider basic Recommend No PEP

volume 2 drug PEP† basic 2- drug PEP warranted

Large Recommend Recommend No PEP

volume basic 2- drug expanded 3 drug warranted

PEP PEP
*HIV positive class 1 -asymptomatic HIV infection or known low viral load

HIV positive class 2_symptomatic HIV infection, AIDS, acute seroconversion, or known high viral load .

§ Less severe- eg solid needle or a superficial injury

More severe- (eg. Large bore needle, deep puncture, visible blood on device or a y

¶ Small volume-i.e. a few drops

Large volume- i.e. a major blood splash

†The designation "consider PEP" indicates that PEP is optional and should be based on an individualized ddecision between the exposed person and the treating clinician

** In source of unknown HIV status _ (eg deceased person with no samples available for HIV testing) Generally no PEP is warranted, however consider 2 drug basic PEP for source with High HIV risk factors. If PEP is offered and taken and the source is later determined to be HIV negative, PEP should be discontinued.

Unknown source-( eg splash from inappropriately disposed blood) Generally no PEP is warranted, however consider 2 drug basic PEP in settings where exposure to HIV infected persons is likely.

Source: MMWR, June 9, 2001

BASIC 2 DRUG PEP : 2 NRTIs for 4 weeks (ZDV+3TC*, d4T+3TC, d4T+ddI)

*preferred regimen

EXPANDED 3 DRUG PEP: 2 NRTIs + 1PI or NNRTI for 4 weeks (Basic +IDV or NFV or EFV)

PEP should be started as early as possible after exposure. It should be given for 4 weeks.

EFV should be avoided in pregnancy . Co existent medical conditions should be noted and appropriate PEP regimen should be given.

2. Wound management-Exposed skin area should be washed with soap and water. The exposed mucosal surfaces like conjunctiva and oral mucosa should be irrigated with clear water.

3. Counselling and follow up –The exposed individual should receive adequate counselling. HIV serology should be done at the time of injury, after 6-8 weeks, 3 months and 6months post exposure.

ABSTRACTS

1. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K, Pierson T, Smith K, Lisziewicz J, Lori F, Flexner C, Quinn TC, Chaisson RE, Rosenberg E, Walker B, Gange S, Gallant J, Siliciano RF. Nat Med 1999;5(5):512-7

Combination therapy for HIV-1 infection can reduce plasma virus to undetectable levels, indicating that prolonged treatment might eradicate the infection. However, HIV-1 can persist in a latent form in resting CD4+ T cells. We measured the decay rate of this latent reservoir in 34 treated adults whose plasma virus levels were undetectable. The mean half-life of the latent reservoir was very long (43.9 months). If the latent reservoir consists of only 1 x 10(5) cells, eradication could take as long as 60 years. Thus, latent infection of resting CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective anti-retroviral therapy.

2. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Egger M, May M, Chene G, Phillips AN, Ledergerber B, Dabis F, Costagliola D, D’Arminio Monforte A, de Wolf F, Reiss P, Lundgren JD, Justice AC, Staszewski S, Leport C, Hogg RS, Sabin CA, Gill MJ, Salzberger B, Sterne JA; ART Cohort Collaboration. Lancet. 2002 Jul 13;360(9327):119-29

BACKGROUND: Insufficient data are available from single cohort studies to allow estimation of the prognosis of HIV-1 infected, treatment-naive patients who start highly active antiretroviral therapy (HAART). The ART Cohort Collaboration, which includes 13 cohort studies from Europe and North America, was established to fill this knowledge gap. METHODS: We analysed data on 12,574 adult patients starting HAART with a combination of at least three drugs. Data were analysed by intention-to-continue-treatment, ignoring treatment changes and interruptions. We considered progression to a combined endpoint of a new AIDS-defining disease or death, and to death alone. The prognostic model that generalised best was a Weibull model, stratified by baseline CD4 cell count and transmission group. FINDINGS During 24,310 person-years of follow up, 1094 patients developed AIDS or died and 344 patients died. Baseline CD4 cell count was strongly associated with the probability of progression to AIDS or death: compared with patients starting HAART with less than 50 CD4 cells/microL, adjusted hazard ratios were 0.74 (95% CI 0.62-0.89) for 50-99 cells/microL, 0.52 (0.44-0.63) for 100-199 cells/microL, 0.24 (0.20-0.30) for 200-349 cells/microL, and 0.18 (0.14-0.22) for 350 or more CD4 cells/microL. Baseline HIV-1 viral load was associated with a higher probability of progression only if 100,000 copies/microL or above. Other independent predictors of poorer outcome were advanced age, infection through injection-drug use, and a previous diagnosis of AIDS. The probability of progression to AIDS or death at 3 years ranged from 3.4% (2.8-4.1) in patients in the lowest-risk stratum for each prognostic variable, to 50% (43-58) in patients in the highest-risk strata. INTERPRETATION: The CD4 cell count at initiation was the dominant prognostic factor in patients starting HAART. Our findings have important implications for clinical management and should be taken into account in future treatment guidelines.

3. Survival Benefit of Initiating Antiretroviral Therapy in HIV-Infected Persons in Different CD4+ Cell Strata. Frank J. Palella, Jr., MD; Maria Deloria-Knoll, PhD; Joan S. Chmiel, PhD; Anne C. Moorman, BSN, MPH; Kathleen C. Wood, BSN; Alan E. Greenberg, MD, MPH; Scott D. Holmberg, MD, MPH, the HIV Outpatient Study (HOPS) Investigators*. Annals of Internal medicine2003;138:620-26

Background: Optimal timing of antiretroviral therapy (ART) initiation for HIV-infected persons remains unclear. Objective: To assess survival benefit of initiating ART at different CD4+ cell counts. Design: Prospective observational study. Setting: U.S. clinics in the HIV Outpatient Study (HOPS). Patients: HIV-infected patients with CD4+ cell counts, plasma HIV RNA viral load, and ART use recorded from January 1994 through March 2002. Measurements: Before initiation of ART, patients were grouped by their CD4+ cell counts into three subgroups: 0.201 to 0.350 x 109 cells/L (n = 399), 0.351 to 0.500 x 109 cells/L (n = 327), and 0.501 to 0.750 x 109 cells/L (n = 122). We compared mortality rates for each CD4+ subgroup among patients who initiated ART and patients who delayed ART until reaching a lower CD4+ subgroup. Results: Mortality rates for 340 patients who initiated ART and 59 who delayed ART in the CD4+ subgroup of 0.201 to 0.350 x 109 cells/L were 15.4 and 56.4 deaths per 1000 person-years, respectively (rate ratio, 0.27 [95% CI, 0.14 to 0.55]; P < 0.001). For the CD4+ subgroup of 0.351 to 0.500 x 109 cells/L, mortality rates for 240 patients who initiated ART and 887 who delayed ART were 10.0 and 16.6 deaths per 1000 person-years, respectively (rate ratio, 0.61 [CI, 0.22 to 1.67]; P = 0.17). For the CD4+ subgroup of 0.501 to 0.750 x 109 cells/L, mortality rates in 55 patients who initiated ART and 67 who delayed ART were 7.5 and 3.1 deaths per 1000 person-years, respectively (rate ratio, 1.20 [CI, 0.17 to 8.53]; P > 0.2). Patients in the 0.201 to 0.350 x 109 cells/L and 0.351 to 0.500 x 109 cells/L CD4+ subgroups who initiated ART were more likely than those who delayed ART to achieve an undetectable HIV viral load (P = 0.03 and 0.04, respectively). Conclusions: Among HIV-infected persons with CD4+ cell counts of 0.201 to 0.350 x 109 cells/L, initiating ART is associated with reduced mortality compared with delaying such therapy. Survival benefits of earlier ART initiation (at CD4+ cell counts of 0.351 to 0.500 x 109 cells/L) are possible

4. Triple-Nucleoside Regimens versus Efavirenz-Containing Regimens for the Initial Treatment of HIV-1 Infection. Roy M. Gulick, M.D., M.P.H., Heather J. Ribaudo, Ph.D., Cecilia M. Shikuma, M.D., Stephanie Lustgarten, M.S., Kathleen E. Squires, M.D., William A. Meyer, III, Ph.D., Edward P. Acosta, Pharm.D., Bruce R. Schackman, Ph.D., Christopher D. Pilcher, M.D., Robert L. Murphy, M.D., William E. Maher, M.D., Mallory D. Witt, M.D., Richard C. Reichman, M.D., Sally Snyder, B.S., Karin L. Klingman, M.D., Daniel R. Kuritzkes, M.D., for the AIDS Clinical Trials Group Study A5095 Team. NEJM 2004;350:1850-61

Background: Regimens containing three nucleoside reverse-transcriptase inhibitors offer an alternative to regimens containing nonnucleoside reverse-transcriptase inhibitors or protease inhibitors for the initial treatment of human immunodeficiency virus type 1 (HIV-1) infection, but data from direct comparisons are limited. Methods: This randomized, double-blind study involved three antiretroviral regimens for the initial treatment of subjects infected with HIV-1: zidovudine–lamivudine–abacavir, zidovudine–lamivudine plus efavirenz, and zidovudine–lamivudine–abacavir plus efavirenz. Results: We enrolled a total of 1147 subjects with a mean baseline HIV-1 RNA level of 4.85 log10 (71,434) copies per milliliter and a mean CD4 cell count of 238 per cubic millimeter were enrolled. A scheduled review by the data and safety monitoring board with the use of prespecified stopping boundaries led to a recommendation to stop the triple-nucleoside group and to present the results in the triple-nucleoside group in comparison with pooled data from the efavirenz groups. After a median follow-up of 32 weeks, 82 of 382 subjects in the triple-nucleoside group (21 percent) and 85 of 765 of those in the combined efavirenz groups (11 percent) had virologic failure; the time to virologic failure was significantly shorter in the triple-nucleoside group (P<0.001). This difference was observed regardless of the pretreatment HIV-1 RNA stratum (at least 100,000 copies per milliliter or below this level; P<0.001 for both comparisons). Changes in the CD4 cell count and the incidence of grade 3 or grade 4 adverse events did not differ significantly between the groups. Conclusions: In this trial of the initial treatment of HIV-1 infection, the triple-nucleoside combination of abacavir, zidovudine, and lamivudine was virologically inferior to a regimen containing efavirenz and two or three nucleosides.

5. Comparison of Sequential Three-Drug Regimens as Initial Therapy for HIV-1 Infection. Gregory K. Robbins, M.D., M.P.H., Victor De Gruttola, Sc.D., Robert W. Shafer, M.D., Laura M. Smeaton, M.S., Sally W. Snyder, B.S., Carla Pettinelli, M.D., Ph.D., Michael P. Dubé, M.D., Margaret A. Fischl, M.D., Richard B. Pollard, M.D., Robert Delapenha, M.D., Linda Gedeon, B.S., Charles van der Horst, M.D., Robert L. Murphy, M.D., Mark I. Becker, Pharm.D., Richard T. D’Aquila, M.D., Stefano Vella, M.D., Thomas C. Merigan, M.D., Martin S. Hirsch, M.D., for the AIDS Clinical Trials Group 384 Team. NEJM2003;349:2293-2303

Background: The optimal sequencing of antiretroviral regimens for the treatment of infection with human immunodeficiency virus type 1 (HIV-1) is unknown. We compared several different antiretroviral treatment strategies. Methods: This multicenter, randomized, partially double-blind trial used a factorial design to compare pairs of sequential three-drug regimens, starting with a regimen including zidovudine and lamivudine or a regimen including didanosine and stavudine in combination with either nelfinavir or efavirenz. The primary end point was the length of time to the failure of the second three-drug regimen. Results: A total of 620 subjects who had not previously received antiretroviral therapy were followed for a median of 2.3 years. Starting with a three-drug regimen containing efavirenz combined with zidovudine and lamivudine (but not efavirenz combined with didanosine and stavudine) appeared to delay the failure of the second regimen, as compared with starting with a regimen containing nelfinavir (hazard ratio for failure of the second regimen, 0.71; 95 percent confidence interval, 0.48 to 1.06), as well as to delay the second virologic failure (hazard ratio, 0.56; 95 percent confidence interval, 0.29 to 1.09), and significantly delayed the failure of the first regimen (hazard ratio, 0.39) and the first virologic failure (hazard ratio, 0.34). Starting with zidovudine and lamivudine combined with efavirenz (but not zidovudine and lamivudine combined with nelfinavir) appeared to delay the failure of the second regimen, as compared with starting with didanosine and stavudine (hazard ratio, 0.68), and significantly delayed both the first and the second virologic failures (hazard ratio for the first virologic failure, 0.39; hazard ratio for the second virologic failure, 0.47), as well as the failure of the first regimen (hazard ratio, 0.35). The initial use of zidovudine, lamivudine, and efavirenz resulted in a shorter time to viral suppression. Conclusions: The efficacy of antiretroviral drugs depends on how they are combined. The combination of zidovudine, lamivudine, and efavirenz is superior to the other antiretroviral regimens used as initial therapy in this study.

6. Maintenance Antiretroviral Therapies in HIV-Infected Subjects with Undetectable Plasma HIV RNA after Triple-Drug Therapy. Diane V. Havlir, M.D., Ian C. Marschner, Ph.D., Martin S. Hirsch, M.D., Ann C. Collier, M.D., Pablo Tebas, M.D., Roland L. Bassett, M.S., John P.A. Ioannidis, M.D., M.K. Holohan, B.A., Randi Leavitt, M.D., Ph.D., Gloria Boone, M.S., Douglas D. Richman, M.D., for The AIDS Clinical Trials Group Study 343 Team. NEJM1998;339:1261-68

Background: Combination antiretroviral therapy with indinavir, zidovudine, and lamivudine can suppress the level of human immunodeficiency virus (HIV) RNA in plasma below the threshold of detection for two years or more. We investigated whether a less intensive maintenance regimen could sustain viral suppression after an initial response to combination therapy. Methods: HIV-infected subjects who had CD4 cell counts greater than 200 per cubic millimeter, who had been treated with indinavir, lamivudine, and zidovudine, and who had less than 200 copies of HIV RNA per milliliter of plasma after 16, 20, and 24 weeks of induction therapy were randomly assigned to receive either continued triple-drug therapy (106 subjects), indinavir alone (103 subjects), or a combination of zidovudine and lamivudine (107 subjects). The primary end point was loss of viral suppression, which was defined as a plasma level of at least 200 copies of HIV RNA per milliliter on two consecutive measurements during maintenance therapy. Results: During maintenance treatment, 23 percent of the subjects receiving indinavir and 23 percent of those receiving zidovudine and lamivudine, but only 4 percent of those receiving all three drugs, had loss of viral suppression (P<0.001 for the comparison between triple-drug therapy and the other two maintenance regimens). Subjects with greater increases in CD4 cell counts during induction therapy, higher viral loads at base line (i.e., at the beginning of induction therapy), and slower rates of viral clearance were at greater risk for loss of viral suppression. The presence of zidovudine-resistance mutations in HIV RNA atbase line was strongly predictive of the loss of viral suppression in subjects treated with zidovudine and lamivudine. Conclusions: The suppression of plasma HIV RNA after six months of treatment with indinavir, zidovudine, and lamivudine is better sustained by the continuation of these three drugs than by maintenance therapy with either indinavir alone or zidovudine and lamivudine.